bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒06‒04
33 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, ECOG analysis.
  2. Molecular patterns identify distinct subclasses of myeloid neoplasia.
  3. Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells.
  4. Towards a Conceptualization of Measurable Residual Disease in Myelodysplastic Syndromes.
  5. Unrelated or haploidentical allogeneic hematopoietic cell transplantation in second complete remission for acute myeloid leukemia-Improved outcomes over time: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party study.
  6. Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT.
  7. Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils.
  8. Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.
  9. Prospective PTCTC Trial of Myeloablative HaploBMT with Post-transplant Cyclophosphamide for Pediatric Acute Leukemias.
  10. Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis, but facilitates termination of emergency (stress) granulopoiesis.
  11. Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis.
  12. CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study.
  13. An old dog has a new trick: somatic exonic deletions in RUNX1 are frequent in AML.
  14. Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
  15. Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency.
  16. Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients.
  17. Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.
  18. Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.
  19. Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.
  20. Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy.
  21. The role of therapy in the outcome of patients with myelofibrosis.
  22. Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma.
  23. A novel 5-gene prognostic signature to improve risk stratification of cytogenetically normal acute myeloid leukemia.
  24. Targeting integrins in drug resistant acute myeloid leukemia.
  25. ABO blood group type and risk of venous thrombosis in essential thrombocythemia.
  26. Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors.
  27. Outcomes with molecularly targeted agents as salvage therapy following frontline venetoclax + hypomethylating agent in adults with acute myeloid leukemia: A multicenter retrospective analysis.
  28. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
  29. Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.
  30. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
  31. Haplodeficiency of the 9p21 Tumor Suppressor Locus Causes Myeloid Disorders Driven by the Bone Marrow Microenvironment.
  32. Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
  33. Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen-sensing pathway from primary familial and congenital polycythaemia.
  1. Blood Adv. 2023 Jun 02. pii: bloodadvances.2022008282. [Epub ahead of print]
    Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, ECOG analysis.
    Sara Zarnegar-Lumley, Todd Alonzo, Robert B Gerbing, Megan Othus, Zhuoxin Sun, Rhonda E Ries, Jim Wang, Amanda R Leonti, Matthew A Kutny, Fabiana Ostronoff, Jerald P Radich, Frederick R Appelbaum, Era L Pogosova-Agadjanyan, Kristen M O'Dwyer, Martin S Tallman, Mark R Litzow, Ehab Atallah, Todd M Cooper, Richard Aplenc, Omar I Abdel-Wahab, Alan S Gamis, Selina M Luger, Harry P Erba, Ross L Levine, E Anders Kolb, Derek L Stirewalt, Soheil Meshinchi, Katherine Tarlock.
      Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, co-occurring mutational profile, and prognostic significance of IDH mutations in AML across the age spectrum. Our cohort included 3,141 patients aged <1 month-88 years treated on CCG/COG (N=1872), SWOG (N=359), ECOG (N=397) trials and in Beat AML (N=333) and TCGA (N=180) genomic characterization cohorts. We retrospectively analyzed patients in four age groups (age range, N): pediatric (0-17, 1744), adolescent/young adult (AYA) (18-39, 444), intermediate-age (40-59, 640), older (≥ 60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (N=288; IDH1 [N=123, 42.7%]; IDH2 [N=165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P<0.001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P=0.368; overall survival [OS]: 50.3% vs 55.4%, P=0.196). IDH mutations frequently co-occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-ITD (22.4%) mutations. In patients with IDHmut AML, survival was significantly improved with co-occurring NPM1 mutation (IDHmut/NPM1mut) compared to the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P<0.001; OS: 66.5% vs 35.2%, P<0.001). Presence of DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Analysis according to age group demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients younger than 60 years; older patients had poor outcomes regardless of NPM1 status. Clinical Trials: NCT00070174, NCT00372593, NCT01371981, NCT00049517, NCT00085709.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008282
  2. Nat Commun. 2023 May 30. 14(1): 3136
    Molecular patterns identify distinct subclasses of myeloid neoplasia.
    Tariq Kewan, Arda Durmaz, Waled Bahaj, Carmelo Gurnari, Laila Terkawi, Hussein Awada, Olisaemeka D Ogbue, Ramsha Ahmed, Simona Pagliuca, Hassan Awada, Yasuo Kutoba, Minako Mori, Ben Ponvilawan, Bayan Al-Share, Bhumika J Patel, Hetty E Carraway, Jacob Scott, Suresh K Balasubramanian, Taha Bat, Yazan Madanat, Mikkael A Sekeres, Torsten Haferlach, Valeria Visconte, Jaroslaw P Maciejewski.
      Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).
    DOI:  https://doi.org/10.1038/s41467-023-38515-4
  3. Adv Biol Regul. 2023 May 23. pii: S2212-4926(23)00020-9. [Epub ahead of print]89 100974
    Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells.
    Salihanur Darici, Heather G Jørgensen, Xu Huang, Valentina Serafin, Ludovica Antolini, Patrizia Barozzi, Mario Luppi, Fabio Forghieri, Sandra Marmiroli, Manuela Zavatti.
      Acute myeloid leukemia is a heterogeneous hematopoietic malignancy, characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells, with poor outcomes. The internal tandem duplication (ITD) mutation of the Fms-like receptor tyrosine kinase 3 (FLT3) (FLT3-ITD) represents the most common genetic alteration in AML, detected in approximately 30% of AML patients, and is associated with high leukemic burden and poor prognosis. Therefore, this kinase has been regarded as an attractive druggable target for the treatment of FLT3-ITD AML, and selective small molecule inhibitors, such as quizartinib, have been identified and trialled. However, clinical outcomes have been disappointing so far due to poor remission rates, also because of acquired resistance. A strategy to overcome resistance is to combine FLT3 inhibitors with other targeted therapies. In this study, we investigated the preclinical efficacy of the combination of quizartinib with the pan PI3K inhibitor BAY-806946 in FLT3-ITD cell lines and primary cells from AML patients. We show here that BAY-806946 enhanced quizartinib cytotoxicity and, most importantly, that this combination increases the ability of quizartinib to kill CD34+ CD38-leukemia stem cells, whilst sparing normal hematopoietic stem cells. Because constitutively active FLT3 receptor tyrosine kinase is known to boost aberrant PI3K signaling, the increased sensitivity of primary cells to the above combination can be the mechanistic results of the disruption of signaling by vertical inhibition.
    Keywords:  Acute myeloid leukemia (AML); BAY-806946; Combination therapy; FLT3-ITD; PI3K/AKT/mTOR; Quizartinib
    DOI:  https://doi.org/10.1016/j.jbior.2023.100974
  4. Blood Adv. 2023 Jun 02. pii: bloodadvances.2023010098. [Epub ahead of print]
    Towards a Conceptualization of Measurable Residual Disease in Myelodysplastic Syndromes.
    Eduard Schulz, Peter D Aplan, Sylvie D Freeman, Steven Z Pavletic.
      Approximately 90% of patients with myelodysplastic syndromes (MDS) have somatic mutations in the malignant cells that are known or suspected to be oncogenic. The genetic risk-stratification of MDS has evolved substantially by the introduction of the clinical-molecular International Prognostic Scoring System (IPSS-M) that establishes next-generation sequencing at diagnosis as a standard of care. Furthermore, the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias has refined MDS diagnostic criteria with the introduction of a new myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) category. Monitoring measurable residual disease (MRD) has historically been used to define remission status, improve relapse prediction, and determine the efficacy of antileukemic drugs in patients with acute and chronic leukemias. However, in contrast to leukemias, assessment of MRD including tracking of patient-specific mutations has not yet been formally defined as a biomarker for MDS. This article summarizes current evidence and challenges, and provides a conceptual framework for incorporating MRD into the treatment of MDS and future clinical trials.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010098
  5. Cancer. 2023 Jun 02.
    Unrelated or haploidentical allogeneic hematopoietic cell transplantation in second complete remission for acute myeloid leukemia-Improved outcomes over time: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party study.
    Rama Al Hamed, Maud Ngoya, Jacques-Emmanuel Galimard, Henrik Sengeloev, Tobias Gedde-Dahl, Aleksandr Kulagin, Uwe Platzbecker, Ibrahim Yakoub-Agha, Jenny L Byrne, Thomas Valerius, Gerard Socie, Nicolaus Kröger, Didier Blaise, Ali Bazarbachi, Jaime Sanz, Fabio Ciceri, Arnon Nagler, Mohamad Mohty.
      BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only cure for acute myeloid leukemia (AML) in second complete remission (CR2). Patients lacking a matched sibling donor (MSD) receive transplants from matched unrelated donors (MUDs), mismatched unrelated donors (MMUDs), haploidentical (haplo) donors, or cord blood.METHODS: This is a retrospective, registry-based European Society for Blood and Marrow Transplantation study that investigates changes in patient- and transplant-related characteristics and posttransplant outcomes over time.
    RESULTS: We identified 3955 adult patients (46.7% female; median age, 52 years [range, 18-78 years]) with AML in CR2 first transplanted between 2005 and 2019 from a MUD 10/10 (61.4%), MMUD 9/10 (21.9%), or haplo donor (16.7%) and followed for 3.7 years. A total of 725 patients were transplanted between 2005 and 2009, 1600 between 2010 and 2014, and 1630 between 2015 and 2019. Over the three time periods, there was a significant increase in patient age (from 48.7 to 53.5 years; p < .001), use of a haplo donor (from 4.6% to 26.4%; p < .001), and use of posttransplant cyclophosphamide (from 0.4% to 29%; p < .001). There was a significant decrease in total body irradiation and in vivo T-cell depletion. In multivariate analysis, transplants performed more recently had better outcomes. Leukemia-free survival (hazard ratio [HR], 0.79; p = .002) and overall survival (HR, 0.73; p < .001) increased over time. Similarly, nonrelapse mortality (HR, 0.64; p < .001) decreased over time. We also observed better graft-vs-host disease (GVHD) rates (acute GVHD II-IV: HR, 0.78; p = .03; GVHD-free, relapse-free survival: HR, 0.69; p < .001).
    CONCLUSIONS: Even in the absence of an MSD, outcomes of allo-HCT in CR2 for AML have significantly improved over time, with most favorable outcomes achieved with a MUD.
    Keywords:  acute myeloid leukemia; allogeneic transplantation; haploidentical donor; second complete remission; transplantation patterns; unrelated donor
    DOI:  https://doi.org/10.1002/cncr.34843
  6. J Hematol Oncol. 2023 May 29. 16(1): 58
    Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT.
    Arnon Nagler, Myriam Labopin, Didier Blaise, Anna Maria Raiola, Lucia Lopez Corral, Stefania Bramanti, Simona Sica, Mi Kwon, Yener Koc, Jiri Pavlu, Alexander Kulagin, Alessandro Busca, Arancha Bermúdez Rodríguez, Péter Reményi, Christoph Schmid, Eolia Brissot, Jaime Sanz, Ali Bazarbachi, Sebastian Giebel, Fabio Ciceri, Mohamad Mohty.
      We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.
    Keywords:  De novo acute myeloid leukemia; Haploidentical allogeneic stem cell transplantation; Post-transplantation cyclophosphamide; Secondary acute myeloid leukemia; Transplantation outcomes
    DOI:  https://doi.org/10.1186/s13045-023-01450-4
  7. Cell Stem Cell. 2023 Jun 01. pii: S1934-5909(23)00174-1. [Epub ahead of print]30(6): 781-799.e9
    Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils.
    Hector Huerga Encabo, Iker Valle Aramburu, Manuel Garcia-Albornoz, Marion Piganeau, Henry Wood, Anna Song, Alessandra Ferrelli, Aneesh Sharma, Carlos M Minutti, Marie-Charlotte Domart, Despoina Papazoglou, Kristian Gurashi, Miriam Llorian Sopena, Robert Goldstone, Todd Fallesen, Qian Wang, Linda Ariza-McNaughton, Daniel H Wiseman, Kiran Batta, Rajeev Gupta, Venizelos Papayannopoulos, Dominique Bonnet.
      Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.
    Keywords:  CRISPR; TET2; clonal hematopoiesis; hematopoietic stem and progenitor cells; immune system; preleukemic neutrophil
    DOI:  https://doi.org/10.1016/j.stem.2023.05.004
  8. Nat Commun. 2023 May 31. 14(1): 3153
    Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation.
    Simona Pagliuca, Carmelo Gurnari, Colin Hercus, Sébastien Hergalant, Sanghee Hong, Adele Dhuyser, Maud D'Aveni, Alice Aarnink, Marie Thérèse Rubio, Pierre Feugier, Francesca Ferraro, Hetty E Carraway, Ronald Sobecks, Betty K Hamilton, Navneet S Majhail, Valeria Visconte, Jaroslaw P Maciejewski.
      Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.
    DOI:  https://doi.org/10.1038/s41467-023-38113-4
  9. Blood Adv. 2023 May 31. pii: bloodadvances.2023010281. [Epub ahead of print]
    Prospective PTCTC Trial of Myeloablative HaploBMT with Post-transplant Cyclophosphamide for Pediatric Acute Leukemias.
    Juan Carlos Fierro-Pineda, Hua-Ling Tsai, Amanda L Blackford, Andrew Cluster, Emi H Caywood, Jignesh Dalal, Jeffrey H Davis, R Maarten Egeler, Jeffrey Huo, Michelle Hudspeth, Amy K Keating, Susan S Kelly, Joerg Krueger, Dean A Lee, Leslie Elaine Lehmann, Lisa Madden, Benjamin R Oshrine, Michael A Pulsipher, Terry J Fry, Heather J Symons.
      Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with post-transplantation cyclophosphamide (PTCy). We report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada in the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC). Nine centers transplanted 32 patients with acute leukemias or MDS with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median age was 12y (range 1-23y). Diagnoses included acute myeloid leukemia (n=15), acute lymphoid leukemia (n=11), mixed lineage leukemia (n=1), and MDS (n=5). Transplant-related mortality (TRM) at 180 days, our primary objective, was 0%. The cumulative incidence (CuI) of acute graft-versus-host disease (aGVHD) grade II at Day 100 was 13%. No patients developed aGVHD grades III-IV. The CuI of moderate-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27/32 (84%). Primary graft failures included three patients that received suboptimal bone marrow grafts, all successfully engrafted after second transplants. The CuI of relapse at 1y was 32%, with more relapse in pre-BMT MRD+ versus MRD- patients. Overall survival at 1y and 2y is 77% and 73%, and event-free survival at 1y and 2y is 68% and 64%, respectively. We demonstrate no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot has led to a phase III trial comparing MAC haploBMT versus HLA-matched unrelated donors, now open in the Children's Oncology Group.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010281
  10. J Biol Chem. 2023 May 27. pii: S0021-9258(23)01895-1. [Epub ahead of print] 104867
    Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis, but facilitates termination of emergency (stress) granulopoiesis.
    Olatundun Williams, Liping Hu, Weiqi Huang, Priyam Patel, Elizabeth T Bartom, Ling Bei, Elizabeth Hjort, Christina Hijiya, Elizabeth A Eklund.
      Age-associated bone marrow changes include myeloid skewing and mutations that lead to clonal hematopoiesis. Molecular mechanisms for these events are ill-defined, but decreased expression of Irf8/Icsbp (interferon regulatory factor 8/interferon consensus sequence binding protein) in aging hematopoietic stem cells (HSCs) may contribute. Irf8 functions as a leukemia suppressor for chronic myeloid leukemia (CML), and young Irf8-/- mice have neutrophilia with progression to acute myeloid leukemia (AML) with aging. Irf8 is also required to terminate emergency granulopoiesis during the innate immune response, suggesting this may be the physiologic counterpart to leukemia suppression by this transcription factor. Identifying Irf8 effectors may define mediators of both events, and thus contributors to age-related bone marrow disorders. In this study, we identified RASSF5 (encoding Nore1) as an Irf8 target gene, and investigated the role of Nore1 in hematopoiesis. We found Irf8 activates RASSF5 transcription and increases Nore1a expression during emergency granulopoiesis. Similar to Irf8-/- mice, we found young Rassf5-/- mice had increased neutrophils and progressed to AML with aging. We identified enhanced DNA-damage, excess clonal hematopoiesis, and a distinct mutation profile in HSCs from aging Rassf5-/- mice compared to wild type. We found sustained emergency granulopoiesis in Rassf5-/- mice, with repeated episodes accelerating AML, also similar to Irf8-/- mice. Identifying Nore1a downstream from Irf8 defines a pathway involved in leukemia suppression and the innate immune response, and suggests a novel molecular mechanism contributing to age-related clonal myeloid disorders.
    Keywords:  apoptosis; gene regulation; hematopoiesis; innate immune response; myeloid leukemia
    DOI:  https://doi.org/10.1016/j.jbc.2023.104867
  11. Elife. 2023 Jun 02. pii: e83004. [Epub ahead of print]12
    Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis.
    Yaeko Nakajima-Takagi, Motohiko Oshima, Junichiro Takano, Shuhei Koide, Naoki Itokawa, Shun Uemura, Masayuki Yamashita, Shohei Andoh, Kazumasa Aoyama, Yusuke Isshiki, Daisuke Shinoda, Atsunori Saraya, Fumio Arai, Kiyoshi Yamaguchi, Yoichi Furukawa, Haruhiko Koseki, Tomokatsu Ikawa, Atsushi Iwama.
      Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPa-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.
    Keywords:  mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.83004
  12. Lancet Haematol. 2023 May 25. pii: S2352-3026(23)00090-X. [Epub ahead of print]
    CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study.
    Pierre Peterlin, Yannick Le Bris, Pascal Turlure, Patrice Chevallier, Audrey Ménard, Marie-Pierre Gourin, Pierre-Yves Dumas, Sylvain Thepot, Ana Berceanu, Sophie Park, Marie-Anne Hospital, Thomas Cluzeau, Simon Bouzy, Jose-Miguel Torregrosa-Diaz, Louis Drevon, Rosa Sapena, Fatiha Chermat, Lionel Ades, Sophie Dimicoli-Salazar, Sylvie Chevret, Marie-Christine Béné, Pierre Fenaux.
      BACKGROUND: CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context.METHODS: This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m2 cytarabine and 44 mg/m2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802.
    FINDINGS: Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death.
    INTERPRETATION: CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients.
    FUNDING: Jazz Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00090-X
  13. Clin Cancer Res. 2023 May 30. pii: CCR-23-1065. [Epub ahead of print]
    An old dog has a new trick: somatic exonic deletions in RUNX1 are frequent in AML.
    Joyeeta Chakraborty, Kristy R Stengel.
      Somatic loss-of-function RUNX1 mutations in AML include missense, nonsense, and frameshift mutations, whereas germline RUNX1 variants in RUNX1-FPDMM also include large exonic deletions. Alternative variant detection approaches revealed that large exonic deletions in RUNX1 are also common in sporadic AML, which has implications for patient stratification and therapeutic decision-making.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1065
  14. Bone Marrow Transplant. 2023 May 30.
    Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
    Arnon Nagler, Myriam Labopin, Ryszard Swoboda, Alexander Kulagin, Andrea Velardi, Jaime Sanz, Hélène Labussière-Wallet, Victoria Potter, Jürgen Kuball, Simona Sica, Elena Parovichnikova, Wolfgang Bethge, Natacha Maillard, Uwe Platzbecker, Friedrich Stölzel, Fabio Ciceri, Mohamad Mohty.
      Second transplantation (HSCT2) is a potential treatment for primary graft failure (pGF). We assessed the outcome of HSCT2, performed between 2000 and 2021, for pGF in 243 patients with acute leukemia. Median age was 44.8 years. Conditioning at first HSCT (HSCT1) was myeloablative (MAC) in 58.4%. Median time from HSCT1 to HSCT2 was 48 days. Donors for HSCT2 were the same as for HSCT1 in 49%. Engraftment post HSCT2 was achieved by 73.7% of patients. The incidence of acute (a) graft versus host disease (GVHD) grades II-IV and III-IV was 23.2 and 8.1%. 5-year total and extensive chronic (c) GVHD was 22.3 and 10.1%. 5-year nonrelapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD free, relapse-free survival (GRFS) was 51.6, 18.8, 29.6, 30.7 and 22.4%, respectively. Infections were the main cause of death. In multivariable analysis, being transplanted at second vs. first remission, lower Karnofsky performance status (KPS; <90) and receiving MAC at HSCT1 were adverse prognostic factors for NRM, LFS, OS, and GRFS, as was increased age for NRM, LFS, OS. We conclude that HSCT2 can rescue about a third of the patients who experienced pGF, but NRM is as high as 50%.
    DOI:  https://doi.org/10.1038/s41409-023-02012-5
  15. Cell Rep. 2023 May 30. pii: S2211-1247(23)00582-X. [Epub ahead of print]42(6): 112571
    Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency.
    Christopher B Mahony, Lucy Copper, Pavle Vrljicak, Boris Noyvert, Chrystala Constantinidou, Sofia Browne, Yi Pan, Claire Palles, Sascha Ott, Martin R Higgs, Rui Monteiro.
      Inherited bone marrow failure associated with heterozygous mutations in GATA2 predisposes toward hematological malignancies, but the mechanisms remain poorly understood. Here, we investigate the mechanistic basis of marrow failure in a zebrafish model of GATA2 deficiency. Single-cell transcriptomics and chromatin accessibility assays reveal that loss of gata2a leads to skewing toward the erythroid lineage at the expense of myeloid cells, associated with loss of cebpa expression and decreased PU.1 and CEBPA transcription factor accessibility in hematopoietic stem and progenitor cells (HSPCs). Furthermore, gata2a mutants show impaired expression of npm1a, the zebrafish NPM1 ortholog. Progressive loss of npm1a in HSPCs is associated with elevated levels of DNA damage in gata2a mutants. Thus, Gata2a maintains myeloid lineage priming through cebpa and protects against genome instability and marrow failure by maintaining expression of npm1a. Our results establish a potential mechanism underlying bone marrow failure in GATA2 deficiency.
    Keywords:  CP: Molecular biology; CP: Stem cell research; DNA damage; GATA2 deficiency; hematopoietic stem cells; single-cell genomics; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2023.112571
  16. PLoS One. 2023 ;18(5): e0286412
    Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients.
    Stella Pearson, Rognvald Blance, Fei Yan, Ya-Ching Hsieh, Bethany Geary, Fabio M R Amaral, Tim C P Somervaille, Kristina Kirschner, Anthony D Whetton, Andrew Pierce.
      Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.
    DOI:  https://doi.org/10.1371/journal.pone.0286412
  17. Br J Haematol. 2023 May 29.
    Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.
    Neil P Shah, Valentín García-Gutiérrez, Antonio Jiménez-Velasco, Sarah M Larson, Susanne Saussele, Delphine Rea, François-Xavier Mahon, Moshe Yair Levy, María Teresa Gómez-Casares, Michael J Mauro, Oumar Sy, Patricia Martin-Regueira, Jeffrey H Lipton.
      Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.
    Keywords:  chronic phase chronic myeloid leukaemia; dasatinib; deep molecular response; major molecular response; treatment-free remission
    DOI:  https://doi.org/10.1111/bjh.18883
  18. Haematologica. 2023 Jun 01.
    Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.
    Thomas Schroeder, Matthias Stelljes, Maximilian Christopeit, Eva Esseling, Christoph Scheid, Jan-Henrik Mikesch, Christina Rautenberg, Paul Jäger, Ron-Patrick Cadeddu, Nadja Drusenheimer, Udo Holtick, Stefan Klein, Rudolf Trenschel, Rainer Haas, Ulrich Germing, Nicolaus Kröger, Guido Kobbe.
      Azacitidine combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide to act synergistically with Azacitidine/DLI to improve outcome. We therefore prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of AML, MDS and CMML. Patients were scheduled for 8 cycles Azacitidine (75 mg/m2 day 1-7), Lenalidomide (2.5 or 5mg, day 1-21) and up to 3 DLI with increasing T cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of MDS (n=24), AML (n=23) or CMML (n=3) received a median of 7 (range, 1 to 8) cycles including 14 patients with 2.5mg and 36 with 5mg Lenalidomide daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lenalidomide dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade II-IV 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lenalidomide can be safely added to Azacitidine/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse. (NCT02472691).
    DOI:  https://doi.org/10.3324/haematol.2022.282570
  19. J Clin Invest. 2023 May 30. pii: e169993. [Epub ahead of print]
    Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.
    Zibo Zhao, Kaixiang Cao, Jun Watanabe, Cassandra N Philips, Jacob M Zeidner, Yukitomo Ishi, Qixuan Wang, Sarah R Gold, Katherine Junkins, Elizabeth T Bartom, Feng Yue, Navdeep S Chandel, Rintaro Hashizume, Issam Ben-Sahra, Ali Shilatifard.
      Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity towards increased purine synthesis in MLL3/4 knockout (KO) mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA sequencing identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag (TMT) proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4 KO cells. Mechanistically, compensation by MLL1/COMPASS underlied these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.
    Keywords:  Colorectal cancer; Epigenetics; Genetics; Metabolism
    DOI:  https://doi.org/10.1172/JCI169993
  20. Br J Haematol. 2023 May 28.
    Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy.
    Shuai-Shuai Ge, Qiao-Cheng Qiu, Hai-Ping Dai, Xiang-Dong Shen, Tian-Mei Wu, Jia-Hui Du, Chao-Ling Wan, Hong-Jie Shen, De-Pei Wu, Sheng-Li Xue, Song-Bai Liu.
      Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.
    Keywords:  FLT3; FLT3 inhibitor; haematological malignancy; kinase activity; mutation spectrum
    DOI:  https://doi.org/10.1111/bjh.18877
  21. Cancer. 2023 May 27.
    The role of therapy in the outcome of patients with myelofibrosis.
    Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Naval G Daver, Koji Sasaki, Helen T Chifotides, Lingsha Zhou, Hagop M Kantarjian, Zeev Estrov, Srdan Verstovsek.
      BACKGROUND: The treatment of patients with myelofibrosis (MF) has evolved in the past decade, as reflected in an increased use of various therapeutic agents that could potentially impact patient outcomes.METHODS: In this retrospective study, the authors evaluated the pattern of therapy and its possible impact on the survival of patients with MF at their institution. Patients (n = 802) with newly diagnosed, chronic, overt MF (MF fibrosis grade ≥2, <10% blasts) seen at their cancer center between 2000 and 2020 were included.
    RESULTS: Overall, 492 of the included patients (61%) initiated MF-directed therapy during follow-up. The most frequent initial therapy was the JAK inhibitor ruxolitinib (44% of treated patients), investigational agents excluding JAK inhibitors (21%), immunomodulatory agents (18%), other investigational JAK inhibitors (10%), and others (7%). Overall survival was superior for patients who received initial ruxolitinib therapy, with a median survival of 72 months versus approximately 50 months for the remaining approaches, excluding the last group. Thirty-two percent of patients required subsequent therapy (n = 159). The longest survival since the start of second-line therapy was observed in patients who initiated salvage ruxolitinib (median, 35 months; 95% CI, 25-45 months).
    CONCLUSIONS: This study demonstrated improved outcomes of patients with MF who received treatment with the JAK inhibitor ruxolitinib.
    Keywords:  JAK inhibitors; initial therapy; myelofibrosis; outcome
    DOI:  https://doi.org/10.1002/cncr.34851
  22. Cancer Discov. 2023 Jun 01. pii: CD-22-0976. [Epub ahead of print]
    Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma.
    Raj K Gopal, Venkata R Vantaku, Apekshya Panda, Bryn Reimer, Sneha Rath, Tsz-Leung To, Adam S Fisch, Murat Cetinbas, Maia Livneh, Michael J Calcaterra, Benjamin J Gigliotti, Kerry A Pierce, Clary B Clish, Dora Dias-Santagata, Peter M Sadow, Lori J Wirth, Gilbert H Daniels, Ruslan I Sadreyev, Sarah E Calvo, Sareh Parangi, Vamsi K Mootha.
      Oncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0976
  23. J Cancer Res Clin Oncol. 2023 Jun 01.
    A novel 5-gene prognostic signature to improve risk stratification of cytogenetically normal acute myeloid leukemia.
    Cong Deng, Tiansheng Zeng, Pei Zhu, Sijie Zhao, Zeyong Huang, Wenhui Huang, Wenjuan Zhang, Xiaojuan Huang, Lin Fu.
      PURPOSE: Prognostic prediction is a challenging task in cytogenetically normal acute myeloid leukemia (CN-AML) patients. In this study, we aimed at developing a novel prognostic signature to predict and stratify the survival of CN-AML patients.METHODS: Using a training dataset (GSE12417), 5-gene prognostic signature was established to predict survival of CN-AML patients. The prognostic performance of this prognostic signature was further validated in testing dataset (TCGA CN-AML cohort) and validation dataset (GSE6891 CN-AML cohort).
    RESULTS: In training, testing and validation datasets, the increased 5-gene risk score was significantly related with inferior overall survival (OS) of patients, and the area under the receiver operating characteristic curve (AUC) demonstrated that our prognostic signature had overall prediction accuracy. The excellent prognostic value of the 5-gene prognostic signature was also supported by the comparison with three previously proposed prognostic models. For the intermediate-risk CN-AML patients and the CN-AML patients with FLT3 or NPM1 mutation, our model could also well dichotomize them into two subgroups with distinct prognosis. Multivariate analysis demonstrated that 5-gene risk score was the only independent risk factor in TCGA CN-AML cohort. Nomogram including the 5-gene risk score performed well in predicting 1-year, 2-year and 3-year OS.
    CONCLUSION: In summary, our novel 5-gene prognostic signature facilitated the improvement in risk stratification of CN-AML patients.
    Keywords:  Cytogenetically normal acute myeloid leukemia; Gene expression profiling; Prognostic signature; Risk stratification
    DOI:  https://doi.org/10.1007/s00432-023-04884-y
  24. Br J Pharmacol. 2023 May 31.
    Targeting integrins in drug resistant acute myeloid leukemia.
    Heather A Ogana, Samantha Hurwitz, Nathan Wei, Eliana Lee, Kayla Morris, Karina Parikh, Yong-Mi Kim.
      Acute myeloid leukemia (AML) continues to have a poor prognosis warranting new therapeutic strategies. The bone marrow (BM) microenvironment consists of niches that interact with not only normal hematopoietic stem cells (HSC), but also leukemia cells like AML. There are many adhesion molecules in the BM microenvironment, integrins have been of central interest. AML cells express integrins which bind to ligands in the microenvironment enabling adhesion of leukemia cells to microenvironment thereby initiating intracellular signaling pathways that are associated with cell migration, cell proliferation, survival, and drug resistance which has been described to mediate cell-adhesion mediated drug-resistance (CAM-DR). Identifying and targeting integrins in AML to interrupt interactions with the microenvironment has been pursued as a strategy to overcome CAM-DR. Here, we focus on the bone marrow microenvironment and review the role of integrins in CAM-DR of AML and in integrin targeting strategies.
    Keywords:  Acute myeloid leukemia; bone marrow microenvironment; cell adhesion molecules; cell adhesion-mediated chemoresistance; integrins; leukemia stem cells; therapy
    DOI:  https://doi.org/10.1111/bph.16149
  25. Br J Haematol. 2023 Jun 02.
    ABO blood group type and risk of venous thrombosis in essential thrombocythemia.
    Omer S Karrar, Maymona Abdelmagid, Alessandro M Vannucchi, Tiziano Barbui, Ayalew Tefferi, Naseema Gangat.
      
    DOI:  https://doi.org/10.1111/bjh.18906
  26. Blood. 2023 Jun 02. pii: blood.2023020257. [Epub ahead of print]
    Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors.
    Catherine Rhee, Elizabeth W Scadden, Lai Ping Wong, Giulia Schiroli, Michael C Mazzola, Phillip L Chea, Hiroki Kato, Friedrich F Hoyer, Meeta Mistry, Bum-Kyu Lee, Jonghwan Kim, Matthias Nahrendorf, Michael Mansour, David Brian Sykes, Ruslan Sadreyev, David T Scadden.
      Myeloid cell heterogeneity is known but whether it is cell-intrinsic or environmentally-directed remains unclear. Here, an inducible/reversible system pausing myeloid differentiation allowed definition of clone-specific functions that clustered monocytes into subsets with distinctive molecular features. These subsets were orthogonal to the classical/non-classical categorization and had inherent, restricted characteristics that did not shift under homeostasis, post-irradiation or with infectious stress. Rather, their functional fate was constrained by chromatin accessibility established at or before the granulocyte-monocyte or monocyte-dendritic progenitor level. Subsets of primary monocytes had differential ability to control distinct infectious agents in vivo. Therefore, monocytes are a heterogeneous population of functionally restricted subtypes defined by the epigenome of their progenitors that are differentially selected by physiologic challenges with limited plasticity to transition from one subset to another.
    DOI:  https://doi.org/10.1182/blood.2023020257
  27. Leuk Res. 2023 May 29. pii: S0145-2126(23)00596-9. [Epub ahead of print]131 107331
    Outcomes with molecularly targeted agents as salvage therapy following frontline venetoclax + hypomethylating agent in adults with acute myeloid leukemia: A multicenter retrospective analysis.
    Vishesh Khanna, Tali Azenkot, Selina Qiuying Liu, Jason Gilbert, Edna Cheung, Kimberly Lau, Daniel A Pollyea, Elie Traer, Brian A Jonas, Tian Y Zhang, Gabriel N Mannis.
      
    Keywords:  AML; Acute myeloid leukemia; Enasidenib; Gilteritinib; HMA; Hypomethylating agents; Ivosidenib; Outcomes; Targeted therapies; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2023.107331
  28. Nature. 2023 May 31.
    Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
    Avishai Gavish, Michael Tyler, Alissa C Greenwald, Rouven Hoefflin, Dor Simkin, Roi Tschernichovsky, Noam Galili Darnell, Einav Somech, Chaya Barbolin, Tomer Antman, Daniel Kovarsky, Thomas Barrett, L Nicolas Gonzalez Castro, Debdatta Halder, Rony Chanoch-Myers, Julie Laffy, Michael Mints, Adi Wider, Rotem Tal, Avishay Spitzer, Toshiro Hara, Maria Raitses-Gurevich, Chani Stossel, Talia Golan, Amit Tirosh, Mario L Suvà, Sidharth V Puram, Itay Tirosh.
      Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.
    DOI:  https://doi.org/10.1038/s41586-023-06130-4
  29. Haematologica. 2023 Jun 01.
    Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.
    Ryotaro Nakamura, Bhavisha A Patel, Soyoung Kim, F Lennie Wong, Saro H Armenian, Emma M Groarke, Daniel A Kessler, Kyle M Hebert, Michael Heim, Mary Eapen, Neal S Young.
      Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compares the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Two treatment periods were defined a priori (2000-2010, 2011-2018), given changes to treatment regimens and differences in length of follow-up. The SMRs of patients treated during the period 2000-2010 and survived 1 year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI 3.20-5.21), and 8.62 (95% CI 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMRs were 2.89 (95% CI 1.54-4.94), 3.12 (95% CI 1.90-4.82), and 4.75 (95% CI 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by 5 years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after 10 years and after 5 years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond 5-years to be comparable to that of the US population.
    DOI:  https://doi.org/10.3324/haematol.2023.282781
  30. Nature. 2023 May 31.
    Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
    Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Böttcher, Alberto Vides, Carlos I Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y Xue, Andreas Mantoulidis, Joachim Bröker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa de Stanchina, Ben Sang, Chuanchuan Li, Darryl B McConnell, Norbert Kraut, Piro Lito.
      KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.
    DOI:  https://doi.org/10.1038/s41586-023-06123-3
  31. Blood. 2023 Jun 02. pii: blood.2022018512. [Epub ahead of print]
    Haplodeficiency of the 9p21 Tumor Suppressor Locus Causes Myeloid Disorders Driven by the Bone Marrow Microenvironment.
    Jue Feng, Pei-Feng Hsu, Eduardo Esteva, Rossella Labella, Yueyang Wang, Alireza Khodadadi-Jamayran, Joseph Nicholas Pucella, Cynthia Z Liu, Arnaldo A Arbini, Aristotelis Tsirigos, Stavroula Kousteni, Boris Reizis.
      The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germline monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the pro-fibrotic chemokine Cxcl13 and osteogenesis- and fibrosis-related multifunctional glycoprotein Osteopontin (OPN)/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease.
    DOI:  https://doi.org/10.1182/blood.2022018512
  32. Nat Commun. 2023 May 29. 14(1): 3100
    Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
    Xuewu Sui, Kun Wang, Kangkang Song, Chen Xu, Jiunn Song, Chia-Wei Lee, Maofu Liao, Robert V Farese, Tobias C Walther.
      Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.
    DOI:  https://doi.org/10.1038/s41467-023-38934-3
  33. Br J Haematol. 2023 May 28.
    Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen-sensing pathway from primary familial and congenital polycythaemia.
    Lucie Sochorcova, Katarina Hlusickova Kapralova, Jana Fialova Kucerova, Dagmar Pospisilova, Daniela Prochazkova, Ondrej Jahoda, Simona Kurekova, Barbora Kralova, Martina Divoka, Jana Navratilova, Jirina Manakova, Eva Kriegova, Karel Indrak, Edgar Faber, Vladimir Divoky, Monika Horvathova.
      Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.
    Keywords:  EPOR; VHL; erythrocytosis; erythroferrone; hepcidin
    DOI:  https://doi.org/10.1111/bjh.18891
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