bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022‒09‒11
thirty papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Differential Prognostic Impact of RUNX1 Mutations According to Frontline Therapy in Patients with Acute Myeloid Leukemia.
  2. Prospective validation of a biomarker-driven response prediction model to romiplostim in lower-risk myelodysplastic neoplasms - results of the EUROPE trial by EMSCO.
  3. Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia.
  4. MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.
  5. Evaluation of the Stellae-123 prognostic gene expression signature in acute myeloid leukemia.
  6. A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges.
  7. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation.
  8. Real-World Data on Chronic Myelomonocytic Leukemia: Clinical and Molecular Characteristics, Treatment, Emerging Drugs, and Patient Outcomes.
  9. Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.
  10. Functional Drug Screening of Small Molecule Inhibitors of Epigenetic Modifiers in Refractory AML Patients.
  11. Characteristics and outcomes of patients with acute promyelocytic leukemia and extreme hyperleukocytosis at presentation.
  12. Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells.
  13. 5'-nucleotidase, cytosolic ii genotype and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.
  14. Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice.
  15. Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.
  16. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study.
  17. The AGILE trial of ivosidenib plus azacitidine versus azacitidine alone: How many limitations is too many?
  18. Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.
  19. ASXL1/2 mutations and myeloid malignancies.
  20. Reduced PU.1 Expression Collaborates with Tet2 Loss to Trigger Myeloid Leukemogenesis.
  21. Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma.
  22. MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?
  23. Effects of chemotherapy dose reductions in overweight patients with acute myeloid leukaemia: A Danish nationwide cohort study.
  24. Frequency and clinical impact of WT1 mutations in the context of CEBPA-mutated acute myeloid leukemia.
  25. The mutational signatures of formalin fixation on the human genome.
  26. Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT.
  27. Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.
  28. Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis.
  29. In APL, noncoding mutations and SNP converge on WT1.
  30. A nomogram using cytogenetics, TP53, and NPM1 mutational status can predict responses to induction chemotherapy in AML.
  1. Am J Hematol. 2022 Sep 10.
    Differential Prognostic Impact of RUNX1 Mutations According to Frontline Therapy in Patients with Acute Myeloid Leukemia.
    Sangeetha Venugopal, Courtney D DiNardo, Sanam Loghavi, Wei Qiao, Farhad Ravandi, Marina Konopleva, Tapan Kadia, Kapil Bhalla, Elias Jabbour, Ghayas C Issa, Walid Macaron, Naval Daver, Gautam Borthakur, Guillermo Montalban-Bravo, Musa Yilmaz, Keyur P Patel, Rashmi Kanagal-Shamanna, Kelly Chien, Abhishek Maiti, Hagop Kantarjian, Nicholas J Short.
      RUNX1-mutated (mRUNX1) acute myeloid leukemia (AML) has historically been associated with poor outcomes in the setting of conventional chemotherapy. The prognostic impact of mRUNX1 AML is not well-established in the current era of lower-intensity treatment regimens incorporating venetoclax. We retrospectively analyzed 907 patients with newly diagnosed AML, including 137 patients with mRUNX1 AML, who underwent first-line therapy with intensive chemotherapy (IC), low-intensity therapy without venetoclax (LIT without VEN), or LIT with VEN. When stratified by RUNX1 status, there was no statistically significant difference in outcomes between mRUNX1 and wild type (wtRUNX1) AML, regardless of therapy received. However, among patients who received LIT with VEN, there was a trend towards superior overall survival (OS) in those with mRUNX1 AML (median OS for mRUNX1 vs wtRUNX1: 25.1 vs 11.3 months; 2-year OS 54% vs 33%; P=0.12). In patients without another adverse-risk cyto-molecular feature, the presence of mRUNX1 conferred inferior OS in patients who received IC (P=0.02) or LIT without VEN (P=0.003) but not in those who received LIT with VEN (mRUNX1 vs wtRUNX1: 25.1 vs 30.0 months; 2-year OS 59% vs 54%; P=0.86). A multivariate analysis showed possible interaction between RUNX1 mutation status and treatment, suggesting a differential prognostic impact of RUNX1 mutations when patients received IC versus LIT with VEN. In summary, the prognostic impact of mRUNX1 AML may be treatment-dependent, and the presence of RUNX1 mutations may not impact clinical outcomes when venetoclax-based regimens are used. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26724
  2. Leukemia. 2022 Sep 07.
    Prospective validation of a biomarker-driven response prediction model to romiplostim in lower-risk myelodysplastic neoplasms - results of the EUROPE trial by EMSCO.
    Anne Sophie Kubasch, Aristoteles Giagounidis, Georgia Metzgeroth, Anna Jonasova, Regina Herbst, Jose Miguel Torregrosa Diaz, Benoit De Renzis, Katharina S Götze, Marie-Luise Huetter-Kroenke, Marie-Pierre Gourin, Borhane Slama, Sophie Dimicoli-Salazar, Pascale Cony-Makhoul, Kamel Laribi, Sophie Park, Katja Jersemann, Dorothea Schipp, Klaus H Metzeler, Oliver Tiebel, Katja Sockel, Silke Gloaguen, Anna Mies, Fatiha Chermat, Christian Thiede, Rosa Sapena, Richard F Schlenk, Pierre Fenaux, Uwe Platzbecker, Lionel Adès.
      The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the 'European Myelodysplastic Neoplasms Cooperative Group' (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.
    DOI:  https://doi.org/10.1038/s41375-022-01669-z
  3. Cells. 2022 Sep 03. pii: 2752. [Epub ahead of print]11(17):
    Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia.
    Shuangshuang Wu, Holly Edwards, Deying Wang, Shuang Liu, Xinan Qiao, Jenna Carter, Yue Wang, Jeffrey W Taub, Guan Wang, Yubin Ge.
      FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.
    Keywords:  AZD5991; FLT3; FLT3-ITD; MRX-2843; Mcl-1; acute myeloid leukemia; gilteritinib
    DOI:  https://doi.org/10.3390/cells11172752
  4. Leuk Lymphoma. 2022 Sep 05. 1-11
    MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.
    Yue Wei, Hong Zheng, Pamela Pennington Lockyer, Faezeh Darbaniyan, Ziyi Li, Rashmi Kanagal-Shamanna, Kelly A Soltysiak, Hui Yang, Irene Ganan-Gomez, Guillermo Montalban-Bravo, Kelly S Chien, Kim-Anh Do, Naval Daver, Guillermo Garcia-Manero.
      Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.
    Keywords:  MDM2; Myelodysplastic syndromes; TP53; chronic myelomonocytic leukemia; hypomethylating agent
    DOI:  https://doi.org/10.1080/10428194.2022.2116932
  5. Front Oncol. 2022 ;12 968340
    Evaluation of the Stellae-123 prognostic gene expression signature in acute myeloid leukemia.
    Adrián Mosquera Orgueira, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Mónica López Riñón, Claudio Cerchione, Adolfo de la Fuente Burguera, Marta Sonia González Pérez, Giovanni Martinelli, Pau Montesinos Fernández, Manuel Mateo Pérez Encinas.
      Risk stratification in acute myeloid leukemia (AML) has been extensively improved thanks to the incorporation of recurrent cytogenomic alterations into risk stratification guidelines. However, mortality rates among fit patients assigned to low or intermediate risk groups are still high. Therefore, significant room exists for the improvement of AML prognostication. In a previous work, we presented the Stellae-123 gene expression signature, which achieved a high accuracy in the prognostication of adult patients with AML. Stellae-123 was particularly accurate to restratify patients bearing high-risk mutations, such as ASXL1, RUNX1 and TP53. The intention of the present work was to evaluate the prognostic performance of Stellae-123 in external cohorts using RNAseq technology. For this, we evaluated the signature in 3 different AML cohorts (2 adult and 1 pediatric). Our results indicate that the prognostic performance of the Stellae-123 signature is reproducible in the 3 cohorts of patients. Additionally, we evidenced that the signature was superior to the European LeukemiaNet 2017 and the pediatric clinical risk scores in the prediction of survival at most of the evaluated time points. Furthermore, integration with age substantially enhanced the accuracy of the model. In conclusion, Stellae-123 is a reproducible machine learning algorithm based on a gene expression signature with promising utility in the field of AML.
    Keywords:  leukemia; machine learning; prediction; risk; survival; transcriptome
    DOI:  https://doi.org/10.3389/fonc.2022.968340
  6. Cancers (Basel). 2022 Aug 28. pii: 4166. [Epub ahead of print]14(17):
    A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges.
    Hassan Awada, Moaath K Mustafa Ali, Bicky Thapa, Hussein Awada, Leroy Seymour, Louisa Liu, Carmelo Gurnari, Ashwin Kishtagari, Eunice Wang, Maria R Baer.
      Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML.
    Keywords:  acute myeloid leukemia; intermediate-risk category; rational therapeutic strategies and challenges
    DOI:  https://doi.org/10.3390/cancers14174166
  7. J Hematol Oncol. 2022 Sep 05. 15(1): 126
    Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation.
    A. M. L. Cooperative Group (AMLCG), Study Alliance Leukemia (SAL)
      BACKGROUND: The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).METHODS: Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal-Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.
    RESULTS: Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).
    CONCLUSION: In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.
    Keywords:  Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; IDH mutations
    DOI:  https://doi.org/10.1186/s13045-022-01339-8
  8. Cancers (Basel). 2022 Aug 25. pii: 4107. [Epub ahead of print]14(17):
    Real-World Data on Chronic Myelomonocytic Leukemia: Clinical and Molecular Characteristics, Treatment, Emerging Drugs, and Patient Outcomes.
    Sandra Castaño-Díez, Mónica López-Guerra, Cristina Bosch-Castañeda, Alex Bataller, Paola Charry, Daniel Esteban, Francesca Guijarro, Carlos Jiménez-Vicente, Carlos Castillo-Girón, Albert Cortes, Alexandra Martínez-Roca, Ana Triguero, José Ramón Álamo, Silvia Beà, Dolors Costa, Dolors Colomer, María Rozman, Jordi Esteve, Marina Díaz-Beyá.
      Despite emerging molecular information on chronic myelomonocytic leukemia (CMML), patient outcome remains unsatisfactory and little is known about the transformation to acute myeloid leukemia (AML). In a single-center cohort of 219 CMML patients, we explored the potential correlation between clinical features, gene mutations, and treatment regimens with overall survival (OS) and clonal evolution into AML. The most commonly detected mutations were TET2, SRSF2, ASXL1, and RUNX1. Median OS was 34 months and varied according to age, cytogenetic risk, FAB, CPSS and CPSS-Mol categories, and number of gene mutations. Hypomethylating agents were administered to 37 patients, 18 of whom responded. Allogeneic stem cell transplantation (alloSCT) was performed in 22 patients. Two-year OS after alloSCT was 60.6%. Six patients received targeted therapy with IDH or FLT3 inhibitors, three of whom attained a long-lasting response. AML transformation occurred in 53 patients and the analysis of paired samples showed changes in gene mutation status. Our real-world data emphasize that the outcome of CMML patients is still unsatisfactory and alloSCT remains the only potentially curative treatment. However, targeted therapies show promise in patients with specific gene mutations. Complete molecular characterization can help to improve risk stratification, understand transformation, and personalize therapy.
    Keywords:  AML transformation; CMML; chronic myelomonocytic leukemia; clonal evolution; gene mutations; hypomethylating agents; prognosis; survival; targeted therapy; treatment
    DOI:  https://doi.org/10.3390/cancers14174107
  9. JCI Insight. 2022 Sep 08. pii: e162016. [Epub ahead of print]7(17):
    Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.
    Baskar Ramdas, Palam Lakshmi Reddy, Raghuveer Singh Mali, Santhosh Kumar Pasupuleti, Ji Zhang, Mark R Kelley, Sophie Paczesny, Chi Zhang, Reuben Kapur.
      Heterozygous mutations in FLT3ITD, TET2, and DNMT3A are associated with hematologic malignancies in humans. In patients, cooccurrence of mutations in FLT3ITD combined with TET2 (TF) or FLT3ITD combined with DNMT3A (DF) are frequent. However, in some rare complex acute myeloid leukemia (AML), all 3 mutations cooccur - i.e., FLT3ITD, TET2, and DNMT3A (TFD). Whether the presence of these mutations in combination result in quantitative or qualitative differences in disease manifestation has not been investigated. We generated mice expressing heterozygous Flt3ITD and concomitant for either heterozygous loss of Tet2 (TF) or Dnmt3a (DF) or both (TFD). TF and DF mice did not induce disease early on, in spite of similar changes in gene expression; during the same time frame, an aggressive form of transplantable leukemia was observed in TFD mice, which was mostly associated with quantitative but not qualitative differences in gene expression relative to TF or DF mice. The gene expression signature of TFD mice showed remarkable similarity to the human TFD gene signature at the single-cell RNA level. Importantly, TFD-driven AML responded to a combination of drugs that target Flt3ITD, inflammation, and methylation in a mouse model, as well as in a PDX model of AML bearing 3 mutations.
    Keywords:  Cytokines; Epigenetics; Hematology; Monocytes
    DOI:  https://doi.org/10.1172/jci.insight.162016
  10. Cancers (Basel). 2022 Aug 24. pii: 4094. [Epub ahead of print]14(17):
    Functional Drug Screening of Small Molecule Inhibitors of Epigenetic Modifiers in Refractory AML Patients.
    Jessica L Dennison, Hassan Al-Ali, Claude-Henry Volmar, Shaun Brothers, Justin Watts, Claes Wahlestedt, Ines Lohse.
      The use of inhibitors of epigenetic modifiers in the treatment of acute myeloid leukemia (AML) has become increasingly appealing due to the highly epigenetic nature of the disease. We evaluated a library of 164 epigenetic compounds in a cohort of 9 heterogeneous AML patients using an ex vivo drug screen. AML blasts were isolated from bone marrow biopsies according to established protocols and treatment response to the epigenetic library was evaluated. We find that 11 histone deacetylase (HDAC) inhibitors, which act upon mechanisms of cell cycle arrest and apoptotic pathways through inhibition of zinc-dependent classes of HDACs, showed efficacy in all patient-derived samples. Other compounds, including bromodomain and extraterminal domain (BET) protein inhibitors, showed efficacy in most samples. Specifically, HDAC inhibitors are already clinically available and can be repurposed for use in AML. Results in this cohort of AML patient-derived samples reveal several epigenetic compounds with high anti-blast activity in all samples, despite the molecular diversity of the disease. These results further enforce the notion that AML is a predominantly epigenetic disease and that similar epigenetic mechanisms may underlie disease development and progression in all patients, despite differences in genetic mutations.
    Keywords:  AML; BET inhibitors; HDAC inhibitors; drug screening; epigenetics; histone modifiers
    DOI:  https://doi.org/10.3390/cancers14174094
  11. Blood Adv. 2022 Sep 08. pii: bloodadvances.2022007126. [Epub ahead of print]
    Characteristics and outcomes of patients with acute promyelocytic leukemia and extreme hyperleukocytosis at presentation.
    Harry J Iland, Nigel H Russell, Richard Dillon, Andre C Schuh, Aditya Tedjaseputra, Andrew H Wei, Asim Khwaja, Steven Knapper, Steven W Lane, John Reynolds, Mary Frances Frances McMullin, Annalise Maria Martin, Peter Tan, David Christopher C Taussig, Anny Wong, John M Taper, Christina Fraga, Richard Kelly, Kiran Tawana, Priyanka Mehta, Alain Mina, Jessica K Altman, Ingolf Mølle, Sudhir Tauro, Eleni Tholouli.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022007126
  12. Cancers (Basel). 2022 Aug 26. pii: 4132. [Epub ahead of print]14(17):
    Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells.
    Florian Renosi, Mary Callanan, Christine Lefebvre.
      Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.
    Keywords:  RUNX1 mutation; acute myeloid leukemia; blastic plasmacytoid dendritic cells neoplasm; mature plasmacytoid dendritic cells proliferation
    DOI:  https://doi.org/10.3390/cancers14174132
  13. Eur J Haematol. 2022 Sep 05.
    5'-nucleotidase, cytosolic ii genotype and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.
    “Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias” (CETLAM group)
      Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: 0.003; HR 2.16, 95%CI 1.29 - 3.61) and lower disease-free survival (DFS) (p: 0.002; HR 2.45, 95%CI 1.41 - 4.27), associated to a higher relapse incidence (p: 0.010; HR 2.23, 95%CI 1.21 - 4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.
    DOI:  https://doi.org/10.1111/ejh.13862
  14. J Clin Invest. 2022 Sep 08. pii: e158869. [Epub ahead of print]
    Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice.
    Sherif Abdelhamed, Melvin E Thomas Iii, Tamara Westover, Masayuki Umeda, Emily Xiong, Chandra Rolle, Michael P Walsh, Huiyun Wu, Jason R Schwartz, Virginia Valentine, Marcus Valentine, Stanley Pounds, Jing Ma, Laura J Janke, Jeffery M Klco.
      SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-β as a potential targetable pathway. Further, we observed non-random genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.
    Keywords:  Hematology; Hematopoietic stem cells; Mouse models
    DOI:  https://doi.org/10.1172/JCI158869
  15. Cancers (Basel). 2022 Sep 02. pii: 4315. [Epub ahead of print]14(17):
    Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.
    Debora Capelli, Diego Menotti, Alessandro Fiorentini, Francesco Saraceni, Attilio Olivieri.
      FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30-40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30-50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.
    Keywords:  Crenolanib; FLT3 inhibitors; FLT3 mutation; Gilteritinib; Midostaurin; Quizartinib; Sorafenib; acute myeloid leukemia; mechanism of resistance; overcoming resistance
    DOI:  https://doi.org/10.3390/cancers14174315
  16. Lancet Haematol. 2022 Sep 02. pii: S2352-3026(22)00216-2. [Epub ahead of print]
    Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study.
    Alexandre Bazinet, Faezeh Darbaniyan, Elias Jabbour, Guillermo Montalban-Bravo, Maro Ohanian, Kelly Chien, Tapan Kadia, Koichi Takahashi, Lucia Masarova, Nicholas Short, Yesid Alvarado, Musa Yilmaz, Farhad Ravandi, Michael Andreeff, Rashmi Kanagal-Shamanna, Irene Ganan-Gomez, Simona Colla, Wei Qiao, Xuelin Huang, Deborah McCue, Bailey Mirabella, Hagop Kantarjian, Guillermo Garcia-Manero.
      BACKGROUND: Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for treatment-naive and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.METHODS: We did a single centre, dose-escalation, dose-expansion, phase 1-2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was used. Patients were treated with intravenous or subcutaneous azacitidine (75 mg/m2) for 5 days and oral venetoclax (100-400 mg) for 7-14 days. The primary outcome was safety and tolerability as well as determination of the maximum tolerated dose and recommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3 study design. All patients who received one dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT04160052. The phase 2 dose-expansion part of the trial is ongoing.
    FINDINGS: Between Nov 12, 2019, and Dec 17, 2021, a total of 23 patients were enrolled in the phase 1 portion of this study (17 [74%] hypomethylating agent naive and six [26%] post-hypomethylating agent failure). 18 (78%) patients were male and five (22%) were female; 21 (91%) were white and two (9%) were Asian. Median follow-up was 13·2 months (IQR 6·8-18·3). The maximum tolerated dose was not reached and the recommended phase 2 dose was established as azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days. The most common grade 3-4 treatment-emergent adverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]), lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths due to sepsis, which were not deemed treatment-related, occurred on the study drugs. The overall response rate was 87% (95% CI 66-97; 20 of 23 patients).
    INTERPRETATION: Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.
    FUNDING: MD Anderson Cancer Center.
    DOI:  https://doi.org/10.1016/S2352-3026(22)00216-2
  17. Transl Oncol. 2022 Sep 02. pii: S1936-5233(22)00182-6. [Epub ahead of print]25 101523
    The AGILE trial of ivosidenib plus azacitidine versus azacitidine alone: How many limitations is too many?
    Anjali Bhatt, Kerrington Powell, Vinay Prasad.
      The AGILE trial compared ivosidenib and azacitidine versus azacitidine for IDH1-mutant acute myeloid leukemia (AML) in elderly patients who were ineligible to receive intensive chemotherapy. While the results of this trial appear encouraging, various concerns become evident from the study design and methodology. First, the AGILE trial did not use post-protocol therapy that met the current standard of care. Second, researchers continued patient enrollment despite knowledge of the survival benefit of azacitidine plus venetoclax shown in the VIALE-A trial, resulting in an inferior control arm. Third, the primary endpoint of AGILE was changed from overall survival (OS) to event-free survival (EFS), and the sample size was reduced to expedite the results. Finally, the trial was halted early based on a non-primary endpoint, which likely led to exaggerated effect size or misleading results. We discuss these limitations and continue to advocate for careful analysis of study design to ensure that appropriate and accurate outcomes are implemented in future studies.
    Keywords:  AGILE; Azacitidine; IDH1-mutant acute myeloid leukemia; Ivosidenib
    DOI:  https://doi.org/10.1016/j.tranon.2022.101523
  18. Cancer Sci. 2022 Sep 10.
    Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.
    Ahmed Elgehama, Yixuan Wang, Ying Yu, Lin Zhou, Zhixiu Chen, Liwei Wang, Lijun Sun, Jian Gao, Biao Yu, Yan Shen, Qiang Xu.
      Small molecule induced degradation of mutant Bcr-Abl1 provides a potential approach to overcome Bcr-Abl1 tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Our previous study reported that a synthetic steroidal glycoside SBF-1 showed remarkable anti-CML activity by inducing the degradation of native Bcr-Abl1 protein. Here, we observed the comparably growth inhibition for SBF-1 in CML cells harboring T315I mutant Bcr-Abl1 in vitro and in vivo. SBF-1 triggered its degradation through disrupting the interaction between protein-tyrosine phosphatase 1B (PTP1B) and Bcr-Abl1. Using SBF-1 as a tool, we found that Tyr46 in PTP1B catalytic domain and Tyr852 in Bcr-Abl1 PH domain are critical for their interaction. Moreover, the phosphorylation of Tyr1086 within Bcr-Abl1 SH2 domain recruited the E3 ubiquitin ligase c-Cbl to catalyze K27-linked ubiquitin chains, which serve as a recognition signal for p62-dependent autophagic degradation. PTP1B dephosphorylated Bcr-Abl1 at Tyr1086 and prevented the recruitment of c-Cbl, leading to the stability of Bcr-Abl1. This study unravels the action mechanism of PTP1B in stabilizing Bcr-Abl1 protein and indicates that the PTP1B-Bcr-Abl1 interaction might be one of druggable target for TKI-resistant CML with point mutations.
    Keywords:  Bcr-Abl1; PTP1B; SBF-1; T315I mutant; chronic myeloid leukemia
    DOI:  https://doi.org/10.1111/cas.15580
  19. J Hematol Oncol. 2022 Sep 06. 15(1): 127
    ASXL1/2 mutations and myeloid malignancies.
    Edward A Medina, Caroline R Delma, Feng-Chun Yang.
      Myeloid malignancies develop through the accumulation of genetic and epigenetic alterations that dysregulate hematopoietic stem cell (HSC) self-renewal, stimulate HSC proliferation and result in differentiation defects. The polycomb group (PcG) and trithorax group (TrxG) of epigenetic regulators act antagonistically to regulate the expression of genes key to stem cell functions. The genes encoding these proteins, and the proteins that interact with them or affect their occupancy at chromatin, are frequently mutated in myeloid malignancies. PcG and TrxG proteins are regulated by Enhancers of Trithorax and Polycomb (ETP) proteins. ASXL1 and ASXL2 are ETP proteins that assemble chromatin modification complexes and transcription factors. ASXL1 mutations frequently occur in myeloid malignancies and are associated with a poor prognosis, whereas ASXL2 mutations frequently occur in AML with t(8;21)/RUNX1-RUNX1T1 and less frequently in other subtypes of myeloid malignancies. Herein, we review the role of ASXL1 and ASXL2 in normal and malignant hematopoiesis by summarizing the findings of mouse model systems and discussing their underlying molecular mechanisms.
    Keywords:  ASXL1/2; Epigenetic regulation; Hematopoiesis; Hematopoietic stem cells; His leukemogenesis; Myeloid malignancies
    DOI:  https://doi.org/10.1186/s13045-022-01336-x
  20. Blood Cancer Discov. 2022 09 06. 3(5): 378-381
    Reduced PU.1 Expression Collaborates with Tet2 Loss to Trigger Myeloid Leukemogenesis.
    Wolfgang E Schleicher, Eric M Pietras.
      The leukemic transformation of hematopoietic stem and progenitor cells in the setting of Tet2 deficiency is driven by PU.1 gene network loss through complementary reduction in PU.1 expression and hypermethylation of ETS loci at the enhancers of PU.1 target genes. See related article by Aivalioti et al., p. 444 (6).
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0100
  21. Am J Hematol. 2022 Sep 10.
    Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma.
    Tracy Lackraj, Sharon Ben Barouch, Jessie J F Medeiros, Stephanie Pedersen, Arnavaz Danesh, Mehran Bakhtiari, Michael Hong, Kit Tong, Jesse Joynt, Andrea Arruda, Mark D Minden, John Kuruvilla, Sita Bhella, Vishal Kukreti, Michael Crump, Anca Prica, Christine Chen, Yangqing Deng, Wei Xu, Trevor J Pugh, Armand Keating, John E Dick, Sagi Abelson, Robert Kridel.
      Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, P=0.043) and from the time of ASCT (51.8% vs. 59.3%, P=0.018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, P=0.445). In terms of specific gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, P=0.011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26726
  22. Cancers (Basel). 2022 Sep 01. pii: 4294. [Epub ahead of print]14(17):
    MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?
    Ilias Pessach, Theodoros Spyropoulos, Eleftheria Lamprianidou, Ioannis Kotsianidis.
      Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.
    Keywords:  acute myeloid leukemia (AML); measurable residual disease (MRD); multiparametric flow cytometry (MFC)
    DOI:  https://doi.org/10.3390/cancers14174294
  23. Br J Haematol. 2022 Sep 09.
    Effects of chemotherapy dose reductions in overweight patients with acute myeloid leukaemia: A Danish nationwide cohort study.
    Daniel Tuyet Kristensen, Lars Børty Nielsen, Lasse Hjort Kyneb Jakobsen, Tove-Christina Choe Kristensen, Lene Østergaard Jepsen, Claudia Schöllkopf, Kim Theilgaard-Mönch, Tarec Christoffer El-Galaly, Anne Stidsholt Roug, Marianne Tang Severinsen.
      Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)-based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy-related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30- and 90-day mortality between DR and non-DR patients. Furthermore, DR did not affect median relapse-free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0-41.7) months; non-DR, 15.0 (12.3-19.3)] with an adjusted difference in five-year restricted mean survival time (Δ5y-RMST) of 0.2 (-8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non-DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y-RMST of 0.8 (-5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject.
    Keywords:  acute leukaemia; chemotherapy; dose reduction; overweight and obesity; survival
    DOI:  https://doi.org/10.1111/bjh.18448
  24. Hematology. 2022 Dec;27(1): 994-1002
    Frequency and clinical impact of WT1 mutations in the context of CEBPA-mutated acute myeloid leukemia.
    Ting Wang, Haiying Hua, Zheng Wang, Biao Wang, Liujun Cao, Wei Qin, Pin Wu, Xiaohui Cai, Hongying Chao, XuZhang Lu.
      INTRODUCTION: Several studies have confirmed that mutations in the Wilms tumor 1 (WT1) gene occur in adult acute myeloid leukemia (AML). However, few data are available regarding the incidence of WT1 mutations in CEBPAmut AML and their impact.METHODS: We retrospectively analyzed the frequency and clinical impact of WT1 mutations in 220 newly diagnosed AML patients with CEBPA mutations(CEBPAmut). Chromosome karyotype analysis was performed by R or G banding method and further confirmed either by fluorescence in situ hybridization (FISH) and/or by multiple reverse transcription polymerase chain reaction (multiple RT-PCR). Mutations were detected with a panel of 112mutational genes using next-generation sequencing (NGS).
    RESULTS: Overall, 30 WT1 mutations were detected in 29 of the 220 CEBPAmut AML patients (13.18%) screened. These mutations clustered overwhelmingly in exon 7 (n=16). WT1 mutations were found to be significantly more frequent in AML patients with double-mutated CEBPA (CEBPAdm) than in AML patients with single-mutated CEBPA (17.36%vs. 8.08%, P = 0.043). Among WT1-mutated patients, the most common co-mutation was FLT3-ITD (n = 7, 24.14%), followed by NRAS (n = 5, 17.24%), CSF3R (n = 4, 13.79%), GATA2 (n = 4, 13.79%), and KIT (n = 4, 13.79%). The most frequent functional pathway was signaling pathways inas many as 62.07% of cases. Notably,the concomitant mutations in epigenetic regulatorswere inversely correlated with WT1 mutations(P = 0.003). CEBPAdm AML patients with WT1 mutations had inferior relapse-free survival, event-free survival and overall survival compared with patients CEBPAdm AML without WT1 mutations (P = 0.002, 0.004, and 0.010, respectively).
    CONCLUSION: Our data showed that WT1 mutations are frequently identified in CEBPAmut AML, especially in CEBPAdm AML. CEBPAmut AML patients with WT1 mutations show distinct spectrum of comutations. In the context of CEBPAdm AML, WT1 mutations predict a poor prognosis.
    Keywords:  Acute myeloid leukemia; CEBPA; WT1; mutation
    DOI:  https://doi.org/10.1080/16078454.2022.2103964
  25. Nat Commun. 2022 09 06. 13(1): 4487
    The mutational signatures of formalin fixation on the human genome.
    Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A Graham, Ville Mustonen.
      Clinical archives of patient material near-exclusively consist of formalin-fixed and paraffin-embedded (FFPE) blocks. The ability to precisely characterise mutational signatures from FFPE-derived DNA has tremendous translational potential. However, sequencing of DNA derived from FFPE material is known to be riddled with artefacts. Here we derive genome-wide mutational signatures caused by formalin fixation. We show that the FFPE-signature is highly similar to signature 30 (the signature of Base Excision Repair deficiency due to NTHL1 mutations), and chemical repair of DNA lesions leads to a signature highly similar to signature 1 (clock-like signature due to spontaneous deamination of methylcytosine). We demonstrate that using uncorrected mutational catalogues of FFPE samples leads to major mis-assignment of signature activities. To correct for this, we introduce FFPEsig, a computational algorithm to rectify the formalin-induced artefacts in the mutational catalogue. We demonstrate that FFPEsig enables accurate mutational signature analysis both in simulated and whole-genome sequenced FFPE cancer samples. FFPEsig thus provides an opportunity to unlock additional clinical potential of archival patient tissues.
    DOI:  https://doi.org/10.1038/s41467-022-32041-5
  26. Bone Marrow Transplant. 2022 Sep 07.
    Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT.
    Alexandros Spyridonidis, Myriam Labopin, Eolia Brissot, Ivan Moiseev, Jan Cornelissen, Goda Choi, Fabio Ciceri, Jan Vydra, Péter Reményi, Montserrat Rovira, Ellen Meijer, Hélène Labussière-Wallet, Didier Blaise, Gwendolyn van Gorkom, Nicolaus Kröger, Yener Koc, Sebastian Giebel, Ali Bazarbachi, Bipin Savani, Arnon Nagler, Mohamad Mohty.
      In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.
    DOI:  https://doi.org/10.1038/s41409-022-01816-1
  27. Transl Res. 2022 Sep 03. pii: S1931-5244(22)00200-6. [Epub ahead of print]
    Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.
    Seyedmohammad Saadatagah, Christie M Ballantyne.
      Age is the most important risk factor for cardiovascular disease and appears to be more than a marker of cumulative exposure to other risk factors such as dyslipidemia and hypertension. With aging, genetic mutations occur that are not present in our germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased chance of developing mosaicism because they are highly proliferative, and mutations with survival benefits can establish clonal populations. Age-related clonal hematopoiesis resulting from somatic mutations was first described ∼25 years ago. The subset of clonal hematopoiesis in which a driver mutation with variant allele frequency of at least 2% occurs in a gene implicated in hematologic malignancies but in the absence of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical consequences of CHIP, including an observed increased risk for cardiovascular disease. Animal models provide insight into the mechanisms by which CHIP increases cardiovascular disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic implications for CHIP in cardiovascular disease prevention.
    Keywords:  ASCVD, atherosclerotic cardiovascular disease; BM, bone marrow; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; CHD, coronary heart disease; CHIP, clonal hematopoiesis of indeterminate potential; CI, confidence interval; Cardiovascular disease; FUSION, Finland–United States Investigation of NIDDM Genetics; Genetics; HR, hazard ratio; HSC, hematopoietic stem cell; LDL, low-density lipoprotein; MGBB, Mass General Brigham Biobank; NLRP3, nucleotide-binding oligomerization domain–like receptor family pyrin domain containing–3; OR, odds ratio; PAD, peripheral artery disease; UKBB, UK Biobank; VAF, variant allele frequency. Non-peer-reviewed references are indicated as (#)(P), preprint and (#)(A), abstract; clonal hematopoiesis of indeterminate potential; interleukin, IL; mutation Abbreviations: AIM2, absent in melanoma–2
    DOI:  https://doi.org/10.1016/j.trsl.2022.08.013
  28. Nat Commun. 2022 Sep 08. 13(1): 5284
    Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis.
    Derek W Brown, Weiyin Zhou, Youjin Wang, Kristine Jones, Wen Luo, Casey Dagnall, Kedest Teshome, Alyssa Klein, Tongwu Zhang, Shu-Hong Lin, Olivia W Lee, Sairah Khan, Jacqueline B Vo, Amy Hutchinson, Jia Liu, Jiahui Wang, Bin Zhu, Belynda Hicks, Andrew St Martin, Stephen R Spellman, Tao Wang, H Joachim Deeg, Vikas Gupta, Stephanie J Lee, Neal D Freedman, Meredith Yeager, Stephen J Chanock, Sharon A Savage, Wael Saber, Shahinaz M Gadalla, Mitchell J Machiela.
      Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.
    DOI:  https://doi.org/10.1038/s41467-022-32986-7
  29. Blood. 2022 Sep 08. 140(10): 1060-1061
    In APL, noncoding mutations and SNP converge on WT1.
    Hsin-Chieh Wu, Hugues de Thé.
      
    DOI:  https://doi.org/10.1182/blood.2022017214
  30. Leuk Lymphoma. 2022 Sep 08. 1-4
    A nomogram using cytogenetics, TP53, and NPM1 mutational status can predict responses to induction chemotherapy in AML.
    Konstantinos Lontos, Anastasia Tsagianni, Mounzer Agha, Anastasios Raptis, Jing-Zhou Hou, Rafic Farah, Robert L Redner, Annie Im, Kathleen A Dorritie, Alison Sehgal, James Rossetti, Nidhi Aggarwal, Melissa Saul, William Gooding, Michael Boyiadzis.
      
    DOI:  https://doi.org/10.1080/10428194.2022.2118532
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