bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022‒04‒03
twenty-two papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia.
  2. Differential prognostic impact of IDH1 and IDH2 mutations in chronic myelomonocytic leukemia.
  3. Epigenetic Downregulation of Socs2 Contributes to Mutant N-Ras-Mediated Hematopoietic Dysregulation.
  4. Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML).
  5. Preclinical and pilot study of type I FLT3 tyrosine kinase inhibitor, crenolanib, with sorafenib in acute myeloid leukemia and FLT3-internal tandem duplication.
  6. Effect of Additional Cytogenetic Abnormalities on Survival in Arsenic Trioxide-Treated Acute Promyelocytic Leukemia.
  7. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
  8. An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms.
  9. Cardiac Events in Patients with Acute Myeloid Leukemia Treated with Venetoclax Combined with Hypomethylating Agents.
  10. Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.
  11. Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
  12. Maximal activation of apoptosis signaling by co-targeting anti-apoptotic proteins in BH3 mimetic-resistant AML and AML stem cells.
  13. Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors.
  14. A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML).
  15. Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells.
  16. Neutralization of SARS-CoV-2 Omicron after vaccination of myelodysplastic syndromes and acute myeloid leukemia patients.
  17. Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair.
  18. Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification.
  19. Clinical and molecular correlates of JAK-inhibitor therapy failure in myelofibrosis: long-term data from a molecularly annotated cohort.
  20. Myeloid neoplasms and clonal hematopoiesis from the RUNX1 perspective.
  21. Molecular basis of haematological disease caused by inherited or acquired RUNX1 mutations.
  22. RNAseqCNV: analysis of large-scale copy number variations from RNA-seq data.
  1. Leukemia. 2022 Mar 30.
    RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia.
    Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, Anne-Sophie Alary, Helene Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondesir, Nicolas Chapuis, Liza Ho, Aicha Boughalem, Marc Lelorc'h, Camille Gobeaux, Michaela Fontenay, Christian Recher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford-Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean-Emmanuel Sarry, Eric Pasmant, Didier Bouscary, Olivier Kosmider, Jerome Tamburini.
      Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01541-0
  2. Leukemia. 2022 Mar 29.
    Differential prognostic impact of IDH1 and IDH2 mutations in chronic myelomonocytic leukemia.
    Connor Walsh, Anthony Hunter, Terra Lasho, Christy Finke, Rhett Ketterling, Rami Komrokji, Ayalew Tefferi, Abhishek Mangaonkar, Matthew Howard, Naseema Gangat, Aref Al-Kali, Najla Al Ali, Eric Padron, Mrinal M Patnaik.
      
    DOI:  https://doi.org/10.1038/s41375-022-01551-y
  3. Dis Model Mech. 2022 Mar 30. pii: dmm.049088. [Epub ahead of print]
    Epigenetic Downregulation of Socs2 Contributes to Mutant N-Ras-Mediated Hematopoietic Dysregulation.
    Xi Jin, Victor Ng, Meiling Zhao, Lu Liu, Tomoyasu Higashimoto, Zheng Hong Lee, Jooho Chung, Victor Chen, Gina Ney, Malathi Kandarpa, Moshe Talpaz, Qing Li.
      RAS mutations occur in a broad spectrum of human hematopoietic malignancies. Activating Ras mutations in blood cells leads to hematopoietic malignancies in mice. In murine hematopoietic stem cells (HSCs), mutant N-RasG12D activates Stat5 to dysregulate stem cell function. However, the underlying mechanism remains elusive. In this study, we demonstrate that Stat5 activation induced by a hyperactive Nras mutant, G12D, is dependent on Jak2 activity. Jak2 is activated in Nras mutant HSC and progenitors (HSPCs) and inhibiting Jak2 with Ruxolitinib significantly decreases Stat5 activation and HSPC hyper-proliferation in vivo in NrasG12D mice. Activation of Jak2-Stat5 is associated with downregulation of Socs2, an inhibitory effector of Jak2/Stat5. Restoration of Socs2 blocks NrasG12D HSC reconstitution in bone marrow transplant recipients. SOCS2 Downregulation is also observed in human acute myeloid leukemia (AML) cells that carry RAS mutations. RAS mutant AML cells exhibited suppression of the enhancer active marker H3K27ac at the SOCS2 locus. Finally, restoration of SOCS2 in RAS mutant AML cells mitigated leukemic growth. Thus, we discovered a novel signaling feedback loop whereby hyperactive Ras signaling activates Jak2/Stat5 via suppression of Socs2.
    Keywords:  Epigenetic regulation; Hematopoietic stem cells; Jak/Stat; Leukemia; Ras signaling; Socs2
    DOI:  https://doi.org/10.1242/dmm.049088
  4. J Cancer Res Clin Oncol. 2022 Mar 29.
    Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML).
    Muhammed Burak Demircan, Tina M Schnoeder, Peter C Mgbecheta, Katrin Schröder, Frank-D Böhmer, Florian H Heidel.
      PURPOSE: Oxidative stress has been linked to initiation and progression of cancer and recent studies have indicated a potential translational role regarding modulation of ROS in various cancers, including acute myeloid leukemia (AML). Detailed understanding of the complex machinery regulating ROS including its producer elements in cancer is required to define potential translational therapeutic use. Based on previous studies in acute myeloid leukemia (AML) models, we considered NADPH oxidase (NOX) family members, specifically NOX4 as a potential target in AML.METHODS: Pharmacologic inhibition and genetic inactivation of NOX4 in murine and human models of AML were used to understand its functional role. For genetic inactivation, CRISPR-Cas9 technology was used in human AML cell lines in vitro and genetically engineered knockout mice for Nox4 were used for deletion of Nox4 in hematopoietic cells via Mx1-Cre recombinase activation.
    RESULTS: Pharmacologic NOX inhibitors and CRISPR-Cas9-mediated inactivation of NOX4 and p22-phox (an essential NOX component) decreased proliferative capacity and cell competition in FLT3-ITD-positive human AML cells. In contrast, conditional deletion of Nox4 enhanced the myeloproliferative phenotype of an FLT3-ITD induced knock-in mouse model. Finally, Nox4 inactivation in normal hematopoietic stem and progenitor cells (HSPCs) caused a minor reduction in HSC numbers and reconstitution capacity.
    CONCLUSION: The role of NOX4 in myeloid malignancies appears highly context-dependent and its inactivation results in either enhancing or inhibitory effects. Therefore, targeting NOX4 in FLT3-ITD positive myeloid malignancies requires additional pre-clinical assessment.
    Keywords:  Acute myeloid leukemia (AML); CRISPR-Cas9; FLT3-ITD; NADPH oxidases (NOX); Nox4; Oxidative stress; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1007/s00432-022-03986-3
  5. Clin Cancer Res. 2022 Mar 28. pii: clincanres.4450.2021. [Epub ahead of print]
    Preclinical and pilot study of type I FLT3 tyrosine kinase inhibitor, crenolanib, with sorafenib in acute myeloid leukemia and FLT3-internal tandem duplication.
    Hiroto Inaba, Jolieke G van Oosterwijk, John C Panetta, Lie Li, Daelynn R Buelow, James S Blachly, Sheila Shurtleff, Ching-Hon Pui, Raul C Ribeiro, Jeffrey E Rubnitz, Stanley Pounds, Sharyn D Baker.
      PURPOSE: To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD).EXPERIMENTAL DESIGN: After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with/without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times/day on days 1-28) and two dose-levels of sorafenib (150 mg/m2/day and 200 mg/m2/day on days 8-28) in 9 pediatric patients with refractory/relapsed FLT3-ITD-positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both pre-clinical and clinical studies.
    RESULTS: The combination of crenolanib and sorafenib in pre-clinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours and led to significantly better leukemia response (P<0.005) and survival (P<0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three-times/week) compared to daily crenolanib or sorafenib (P<0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities and 3 complete remissions (1 with incomplete count recovery) and 1 partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a non-significant decrease during treatment (45.0 L/h/m2,40.5 L/h/m2, and 20.3 L/h/m2 on days 1, 7, and 14, respectively) without drug-drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L).
    CONCLUSIONS: The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-4450
  6. Blood Adv. 2022 Mar 29. pii: bloodadvances.2021006682. [Epub ahead of print]
    Effect of Additional Cytogenetic Abnormalities on Survival in Arsenic Trioxide-Treated Acute Promyelocytic Leukemia.
    Zachary D Epstein-Peterson, Andriy Derkach, Susan Geyer, Krzysztof Mrózek, Jessica Kohlschmidt, Jae H Park, Sridevi Rajeeve, Eytan M Stein, Yanming Zhang, Harry J Iland, Lynda J Campbell, Richard A Larson, Xavier Poiré, Bayard L Powell, Wendy Stock, Richard M Stone, Martin S Tallman.
      Frontline arsenic trioxide (ATO)-based treatment regimens achieve high rates of long-term relapse-free survival in treating acute promyelocytic leukemia (APL) and form the current standard of care. Refining prognostic estimates for newly diagnosed patients treated with ATO-containing regimens remains important to continue to improve outcomes and identify patients achieving suboptimal outcomes. We performed a pooled analysis of exclusively ATO-treated patients at a single academic institution and from the ALLG APML4 and Alliance C9710 studies to determine the prognostic importance of additional cytogenetic abnormalities and/or complex karyotype. We demonstrate inferior event-free survival for patients harboring complex karyotype [hazard ratio (HR): 3.74, 95% confidence interval: 1.63-8.56, P = 0.002] but not for patients harboring additional cytogenetic abnormalities (HR 2.13, 95% CI: 0.78-5.82, P = 0.142). These data support the role for full karyotypic analysis for all patients with APL and indicate a need for novel treatment strategies to overcome this adverse effect for APL harboring complex karyotype.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006682
  7. Exp Cell Res. 2022 Mar 25. pii: S0014-4827(22)00105-7. [Epub ahead of print]415(1): 113112
    IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
    Yanjie Zhang, Hezhou Guo, Zhaoli Zhang, Wei Lu, Jiang Zhu, Jun Shi.
      Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36-cells, CD36+ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36+ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.
    Keywords:  Acute myeloid leukemia; CD36; Chemoresistance; Fatty acid uptake; Interleukin-6
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113112
  8. Br J Haematol. 2022 Mar 30.
    An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms.
    Graciela Rabadan Moraes, Florence Pasquier, Christophe Marzac, Eric Deconinck, Carlotta Caterina Damanti, Gwendoline Leroy, Mira El-Khoury, Wassim El Nemer, Jean-Jacques Kiladjian, Hana Raslova, Albert Najman, William Vainchenker, Caroline Marty, Christine Bellanné-Chantelot, Isabelle Plo.
      Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.
    Keywords:   EPOR P488S ; JAK2 V617F ; familial myeloproliferative neoplasms; germline factor; predisposition
    DOI:  https://doi.org/10.1111/bjh.18165
  9. Blood Adv. 2022 Mar 31. pii: bloodadvances.2022007333. [Epub ahead of print]
    Cardiac Events in Patients with Acute Myeloid Leukemia Treated with Venetoclax Combined with Hypomethylating Agents.
    Isla M Johnson, Evandro D Bezerra, Faiqa Farrukh, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede Begna, Mark R Litzow, William J Hogan, Mithun Vinod Shah, Mrinal M Patnaik, Ayalew Tefferi, Naseema Gangat.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022007333
  10. J Clin Oncol. 2022 Mar 29. JCO2101612
    Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.
    Jessica A Pollard, Todd A Alonzo, Robert Gerbing, Patrick Brown, Elizabeth Fox, John Choi, Brian Fisher, Betsy Hirsch, Samir Kahwash, Kelly Getz, John Levine, Lisa Eidenschink Brodersen, Michael R Loken, Susana Raimondi, Katherine Tarlock, Andrew Wood, Lillian Sung, E Anders Kolb, Alan Gamis, Soheil Meshinchi, Richard Aplenc.
      PURPOSE: High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.MATERIALS AND METHODS: Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.
    RESULTS: The maximum tolerated dose of sorafenib was 200 mg/m2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010).
    CONCLUSION: Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.
    DOI:  https://doi.org/10.1200/JCO.21.01612
  11. Br J Pharmacol. 2022 Mar 30.
    Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
    Xinrong Xiang, Rui Bao, Yu Wu, Youfu Luo.
      Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different catogory, we comprehensively reviewed the role of mitochondrial proteases in AML. This review highlights some 'powerful' mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.
    Keywords:  acute myeloid leukemia; mitochondrial metabolism; mitochondrial proteases; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/bph.15844
  12. Mol Cancer Ther. 2022 Apr 01. pii: molcanther.0690.2021. [Epub ahead of print]
    Maximal activation of apoptosis signaling by co-targeting anti-apoptotic proteins in BH3 mimetic-resistant AML and AML stem cells.
    Bing Z Carter, Po Yee Mak, Wenjing Tao, Qi Zhang, Vivian Ruvolo, Vinitha M Kuruvilla, Xiangmeng Wang, Duncan H Mak, Venkata L Battula, Marina Konopleva, Elias J Jabbour, Paul E Hughes, Xiaoyue Chen, Phuong K Morrow, Michael Andreeff.
      MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We here demonstrate ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant AML. Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Co-targeting BCL-2 and MCL-1 was highly synergistic in AML cell lines with intrinsic or acquired resistance to BH3 mimetics or engineered to genetically-overexpress BCL-2 or BCL-2A1 or downregulate BAX. The combination effectively eliminated primary AML blasts and stem/progenitor cells resistant to or relapsed after venetoclax-based therapy irrespective of mutations and cytogenetic abnormalities. Venetoclax and AMG176 combination markedly suppressed anti-apoptotic BCL-2 proteins and AML stem/progenitor cells and dramatically extended mouse survival (median 336 vs control 126 d, P&lt;0.0001) in a PDX model developed from a venetoclax/hypomethylating agent therapy-resistant AML patient. However, decreased BAX levels in the bone marrow residual leukemia cells after 4-wk combination treatment may represent a resistance mechanism that contributed to their survival. Enhanced anti-leukemia activity was also observed in a PDX model of monocytic AML, known to be resistant to venetoclax therapy. Our results support co-dependence on multiple anti-apoptotic BCL-2 proteins and suppression of BAX as mechanisms of AML resistance to individual BH3 mimetics. Co-targeting of MCL-1 and BCL-2 eliminates otherwise apoptosis-resistant cells.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-21-0690
  13. Am J Hematol. 2022 Mar 31.
    Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors.
    Fadi G Haddad, Koji Sasaki, Ghayas C Issa, Guillermo Garcia-Manero, Farhad Ravandi, Tapan Kadia, Jorge Cortes, Marina Konopleva, Naveen Pemmaraju, Yesid Alvarado, Musa Yilmaz, Gautam Borthakur, Courtney DiNardo, Nitin Jain, Naval Daver, Nicholas J Short, Elias Jabbour, Hagop Kantarjian.
      Tyrosine kinase inhibitors (TKIs) discontinuation in patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph-positive CML) is increasingly considered. We aim to evaluate the outcome of patients with CML who discontinued TKIs, and determine the factors associated with differences in the success rates of treatment-free remission (TFR). Patients with Ph-positive CML treated between October 1999 and February 2017 who discontinued therapy were analyzed. A major molecular response (MMR) was defined as BCR-ABL1/ABL1 ratio on the International Scale ≤0.1%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response, and conducted a multivariate analysis for factors associated with loss of MMR. Two-hundred and eighty-four patients were analyzed; 199 patients (70%) electively discontinued TKIs. At a median follow-up of 36 months (95% CI, 32-40) after TKI discontinuation, 53 patients (19%) lost MMR. The estimated 5-year TFR rate was 79%. All but one patient regained MMR after resuming therapy. The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 <5 years (87% vs. 92% vs. 64%; P <0.0001). By multivariate analysis, only the duration of MR4 or MR4.5 ≥5 years before stopping treatment was associated with a lower risk of loss of MMR. In summary, treatment-free remission is safe and feasible in patients with Ph-positive CML on TKI therapy. Achieving MR4 or MR4.5 for at least 5 years is correlated with a better outcome. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26550
  14. Ther Adv Hematol. 2022 ;13 20406207221081637
    A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML).
    Silvia Park, Daehun Kwag, Tong Yoon Kim, Jong Hyuk Lee, Joon Yeop Lee, Gi June Min, Sung Soo Park, Seung-Ah Yahng, Young-Woo Jeon, Seung-Hwan Shin, Jae-Ho Yoon, Sung-Eun Lee, Byung Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong Wook Lee, Hee-Je Kim.
      Background: Evidence that a venetoclax (VEN)-combined regimen is effective in relapsed/refractory acute myeloid leukemia (R/R AML) is emerging. However, it is unknown how VEN-combined low intensity treatment compares to intensive chemotherapy (IC) in medically fit patients with R/R AML.Methods: We compared AML patients who received IC (n = 89) to those who received a VEN in combination with hypomethylating agents or low dose cytarabine (VEN combination) (n = 54) as their first- or second-line salvage after failing anthracycline-containing intensive chemotherapy.
    Results: The median age was 49 years, and significantly more patients in the VEN combination group were in their second salvage and had received prior stem cell transplantation (SCT). Overall response rates including CR, CRi, and MLFS were comparable (44.0% for IC vs. 59.3% for VEN combination, p = 0.081), but VEN combination group compared to IC group tended to show lower treatment related mortality. The rate of bridging to SCT was the same (68.5%), but the percentage of SCT at blast clearance was significantly higher in the VEN-combined group (62.3% vs. 86.5%, p = 0.010). After median follow-up periods of 22.5 (IC) and 11.3 months (VEN combination), the median overall survival was 8.9 (95% CI, 5.4-12.4) and 12.4 months (95% CI, 9.5-15.2) (p = 0.724), respectively.
    Conclusion: VEN combination provides a comparable anti-leukemic response and survival to salvage IC, and provide a bridge to SCT with better disease control in medically-fit patients with R/R AML.
    Keywords:  acute myeloid leukemia; intensive chemotherapy; relapsed/refractory; salvage chemotherapy; venetoclax combination
    DOI:  https://doi.org/10.1177/20406207221081637
  15. Clin Cancer Res. 2022 Mar 29. pii: clincanres.3594.2021. [Epub ahead of print]
    Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells.
    Giulia Corradi, Barbara Bassani, Giorgia Simonetti, Sabina Sangaletti, Jayakumar Vadakekolathu, Maria Chiara Fontana, Martina Pazzaglia, Alessandro Gulino, Claudio Tripodo, Gianluca Cristiano, Lorenza Bandini, Emanuela Ottaviani, Darina Ocadlikova, Milena Piccioli, Giovanni Martinelli, Mario Paolo Colombo, Sergio Rutella, Michele Cavo, Marilena Ciciarello, Antonio Curti.
      PURPOSE: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis.EXPERIMENTAL DESIGN: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone.
    RESULTS: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment.
    CONCLUSIONS: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3594
  16. Blood. 2022 Mar 28. pii: blood.2022016087. [Epub ahead of print]
    Neutralization of SARS-CoV-2 Omicron after vaccination of myelodysplastic syndromes and acute myeloid leukemia patients.
    Lorenza Bellusci, Gabrielle Grubbs, Pragya Srivastava, Michael J Nemeth, Elizabeth A Griffiths, Hana Golding, Surender Khurana.
      
    DOI:  https://doi.org/10.1182/blood.2022016087
  17. Blood. 2022 Mar 25. pii: blood.2021014103. [Epub ahead of print]
    Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair.
    Silvia Alvarez, Ana da Silva Almeida, Robert Albero, Mayukh Biswas, Angelica Barreto-Galvez, Thomas S Gunning, Anam Shaikh, Tomas Aparicio, Agnieszka Anya Wendorff, Erich Piovan, Pieter Van Vlierberghe, Steven Gygi, Jean Gautier, Advaitha Madireddy, Adolfo A Ferrando.
      The Plant Homeodomain 6 gene (PHF6) encodes a nucleolar and chromatin-associated leukemia tumor suppressor with proposed roles in transcription regulation. However, specific molecular mechanisms controlled by PHF6 remain rudimentarily understood. Here we show that PHF6 engages multiple nucleosome remodeling protein complexes including NuRD, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, following DNA damage, PHF6 localizes to sites of DNA injury and its loss impairs the resolution of DNA breaks with consequent accumulation of single- and double-stranded DNA lesions. Native chromatin immunoprecipitation sequencing analyses reveal that PHF6 specifically associates with difficult to replicate heterochromatin at satellite DNA regions enriched in Histone H3 lysine 9 trimethyl marks (H3K9me3) and single molecule locus-specific analyses identify PHF6 as an important regulator of genomic stability at fragile sites. These results extend our understanding of the molecular mechanisms controlling HSC homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics and DNA repair.
    DOI:  https://doi.org/10.1182/blood.2021014103
  18. Nat Commun. 2022 Mar 28. 13(1): 1640
    Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification.
    Ting Liu, Jianan Rao, Wenting Hu, Bowen Cui, Jiaoyang Cai, Yuhan Liu, Huiying Sun, Xiaoxiao Chen, Yanjing Tang, Jing Chen, Xiang Wang, Han Wang, Wubin Qian, Binchen Mao, Sheng Guo, Ronghua Wang, Yu Liu, Shuhong Shen.
      Studies have revealed key genomic aberrations in pediatric acute myeloid leukemia (AML) based on Western populations. It is unknown to what extent the current genomic findings represent populations with different ethnic backgrounds. Here we present the genomic landscape of driver alterations of Chinese pediatric AML and discover previously undescribed genomic aberrations, including the XPO1-TNRC18 fusion. Comprehensively comparing between the Chinese and Western AML cohorts reveal a substantially distinct genomic alteration profile. For example, Chinese AML patients more commonly exhibit mutations in KIT and CSF3R, and less frequently mutated of genes in the RAS signaling pathway. These differences in mutation frequencies lead to the detection of previously uncharacterized co-occurring mutation pairs. Importantly, the distinct driver profile is clinical relevant. We propose a refined prognosis risk classification model which better reflected the adverse event risk for Chinese AML patients. These results emphasize the importance of genetic background in precision medicine.
    DOI:  https://doi.org/10.1038/s41467-022-29336-y
  19. Leukemia. 2022 Mar 26.
    Clinical and molecular correlates of JAK-inhibitor therapy failure in myelofibrosis: long-term data from a molecularly annotated cohort.
    James T England, Caroline J McNamara, James A Kennedy, Jose-Mario Capo-Chichi, Jingyue Huang, Andrea Arruda, Taylor Nye, Verna Cheung, Jaime O Claudio, Dawn Maze, Hassan Sibai, Anne Tierens, Hubert Tsui, Aniket Bankar, Wei Xu, Tracy Stockley, Vikas Gupta.
      
    DOI:  https://doi.org/10.1038/s41375-022-01544-x
  20. Leukemia. 2022 Mar 30.
    Myeloid neoplasms and clonal hematopoiesis from the RUNX1 perspective.
    Yoshihiro Hayashi, Yuka Harada, Hironori Harada.
      RUNX1 is a critical transcription factor for the emergence of definitive hematopoiesis and the precise regulation of adult hematopoiesis. Dysregulation of its regulatory network causes aberrant hematopoiesis. Recurrent genetic alterations in RUNX1, including chromosomal translocations and mutations, have been identified in both inherited and sporadic diseases. Recent genomic studies have revealed a vast mutational landscape surrounding genetic alterations in RUNX1. Accumulating pieces of evidence also indicate the leukemogenic role of wild-type RUNX1 in certain situations. Based on these efforts, part of the molecular mechanisms of disease development as a consequence of dysregulated RUNX1-regulatory networks have become increasingly evident. This review highlights the recent advances in the field of RUNX1 research and discusses the critical roles of RUNX1 in hematopoiesis and the pathobiological function of its alterations in the context of disease, particularly myeloid neoplasms, and clonal hematopoiesis.
    DOI:  https://doi.org/10.1038/s41375-022-01548-7
  21. Exp Hematol. 2022 Mar 24. pii: S0301-472X(22)00129-1. [Epub ahead of print]
    Molecular basis of haematological disease caused by inherited or acquired RUNX1 mutations.
    Sophie G Kellaway, Daniel Jl Coleman, Peter N Cockerill, Manoj Raghavan, Constanze Bonifer.
      The transcription factor RUNX1 is essential for correct hematopoietic development as in its absence in the germ line blood stem cells are not formed. RUNX1 orchestrates dramatic changes in the chromatin landscape at the onset of stem cell formation which set the stage for both stem self-renewal and further differentiation. However, once blood stem cells are formed, the mutation of the RUNX1 gene is not lethal but can lead to various hematopoietic defects and a predisposition to cancer. Here we summarize the current literature of inherited and acquired RUNX1 mutations with a particular emphasis on mutations that alter the structure of the RUNX1 protein itself and place these changes in the context of what is known about RUNX1 function. We also summarize which mutant RUNX1 proteins are actually expressed in cells and discuss the molecular mechanism of how such variants reprogram the epigenome setting stem cells on the path to malignancy.
    DOI:  https://doi.org/10.1016/j.exphem.2022.03.009
  22. Leukemia. 2022 Mar 29.
    RNAseqCNV: analysis of large-scale copy number variations from RNA-seq data.
    Jan Bařinka, Zunsong Hu, Lu Wang, David A Wheeler, Delaram Rahbarinia, Clay McLeod, Zhaohui Gu, Charles G Mullighan.
      Transcriptome sequencing (RNA-seq) is widely used to detect gene rearrangements and quantitate gene expression in acute lymphoblastic leukemia (ALL), but its utility and accuracy in identifying copy number variations (CNVs) has not been well described. CNV information inferred from RNA-seq can be highly informative to guide disease classification and risk stratification in ALL due to the high incidence of aneuploid subtypes within this disease. Here we describe RNAseqCNV, a method to detect large scale CNVs from RNA-seq data. We used models based on normalized gene expression and minor allele frequency to classify arm level CNVs with high accuracy in ALL (99.1% overall and 98.3% for non-diploid chromosome arms, respectively), and the models were further validated with excellent performance in acute myeloid leukemia (accuracy 99.8% overall and 99.4% for non-diploid chromosome arms). RNAseqCNV outperforms alternative RNA-seq based algorithms in calling CNVs in the ALL dataset, especially in samples with a high proportion of CNVs. The CNV calls were highly concordant with DNA-based CNV results and more reliable than conventional cytogenetic-based karyotypes. RNAseqCNV provides a method to robustly identify copy number alterations in the absence of DNA-based analyses, further enhancing the utility of RNA-seq to classify ALL subtype.
    DOI:  https://doi.org/10.1038/s41375-022-01547-8
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