bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–12–25
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling.
  2. Flotetuzumab and other T-Cell Immunotherapies Upregulate MHC Class II Expression on Acute Myeloid Leukemia Cells.
  3. Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.
  4. Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.
  5. Molecular genetic characterization of Philadelphia chromosome-positive acute myeloid leukemia.
  6. The tetraspanin CD53 protects stressed hematopoietic stem cells via promotion of DREAM complex- mediated quiescence.
  7. Prognostic impact of the AML ELN2022 risk classification in patients undergoing allogeneic stem cell transplantation.
  8. Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G-CSF based regimens.
  9. Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome: A large single institution analysis of 1774 patients.
  10. Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model.
  11. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.
  12. High rate of invasive fungal infections during early cycles of azacitidine for patients with acute myeloid leukemia.
  13. Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates.
  14. Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis.
  15. Efficient combinatorial targeting of RNA transcripts in single cells with Cas13 RNA Perturb-seq.
  16. The Latest Breakthroughs in Immunotherapy for Acute Myeloid Leukemia, with a Special Focus on NKG2D Ligands.
  17. TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis.
  18. Cord blood versus haploidentical transplantations for non-remission acute myeloid leukaemia: Authors' reply.
  19. Chimeric Antigen Receptor T-cell Therapy for Acute Myeloid Leukemia.
  20. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances.
  21. Acute myeloid leukemia resistant to venetoclax-based therapy: What does the future hold?
  22. FLT3-ITD Measurable Residual Disease Monitoring in Acute Myeloid Leukemia Using Next-Generation Sequencing.
  23. Biology and therapeutic targeting of molecular mechanisms in MPN.
  24. Crizotinib has Preclinical Efficacy in Philadelphia-negative Myeloproliferative Neoplasms.
  25. Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia.
  26. Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.
  27. mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.
  28. miR-495-3p Sensitizes BCR-ABL1 Expressing Leukemic cells to Tyrosine Kinase Inhibitors by Targeting Multidrug Resistance 1 Gene including in T315I Mutated cells.
  29. Predicting In-Hospital Mortality After Acute Myeloid Leukemia Therapy: Through Supervised Machine Learning Algorithms.
  30. Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis.
  31. Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters.
  1. Leukemia. 2022 Dec 22.
    Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling.
    Nicholas R Anderson, Vipul Sheth, Hui Li, Mason W Harris, Shaowei Qiu, David K Crossman, Harish Kumar, Puneet Agarwal, Takashi Nagasawa, Andrew J Paterson, Robert S Welner, Ravi Bhatia.
      Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.
    DOI:  https://doi.org/10.1038/s41375-022-01798-5
  2. Blood. 2022 Dec 23. pii: blood.2022017795. [Epub ahead of print]
    Flotetuzumab and other T-Cell Immunotherapies Upregulate MHC Class II Expression on Acute Myeloid Leukemia Cells.
    Joseph Cataquiz Rimando, Ezhilarasi Chendamarai, Michael P Rettig, Reyka G Jayasinghe, Matthew Christopher, Julie K Ritchey, Stephanie Christ, Miriam Kim, Ezio Bonvini, John F DiPersio.
      Acute myeloid leukemia (AML) relapse is one of the most common and significant adverse events following allogeneic hematopoietic cell transplantation (allo-HCT). Downregulation of major histocompatibility class II (MHC-II) surface expression on AML blasts may represent a mechanism of escape from the graft-versus-malignancy effect and facilitate relapse. We hypothesized that T-cell immunotherapies targeting AML antigens would upregulate MHC-II surface expression via localized release of interferon gamma (IFN-γ), a protein known to upregulate MHC-II expression via JAK-STAT signaling. We demonstrate that flotetuzumab (FLZ), a CD123xCD3 bispecific DART® molecule, and chimeric antigen receptor expressing T-cells (CAR-T) targeting CD123, CD33, or CD371 upregulate MHC-II surface expression in vitro on a THP-1 AML cell line with intermediate MHC-II expression and four primary AML samples from patients relapsing after HCT with low MHC-II expression. We additionally show that FLZ upregulates MHC-II expression in a patient-derived xenograft model and in relapsed/refractory AML patients treated with flotetuzumab in a clinical trial. Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression.
    DOI:  https://doi.org/10.1182/blood.2022017795
  3. Cancer. 2022 Dec 21.
    Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.
    Talha Badar, Mark R Litzow, Rory M Shallis, Anand Patel, Antoine N Saliba, Madelyn Burkart, Jan P Bewersdorf, Maximilian Stahl, Guilherme Sacchi De Camargo Correia, Guru Subramanian Guru Murthy, Yasmin Abaza, Adam Duvall, Danielle Bradshaw, Vamsi Kota, Shira Dinner, Aaron D Goldberg, Neil Palmisiano, Aref Al Kali, Ehab Atallah.
       BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML.
    METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients.
    RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant.
    CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.
    Keywords:  TP53mutation; acute myeloid leukemia (AML); allogeneic hematopoietic stem cell transplantation (allo-HSCT); disparities in leukemia; structural racism
    DOI:  https://doi.org/10.1002/cncr.34604
  4. Blood. 2022 Dec 22. pii: blood.2022018092. [Epub ahead of print]
    Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.
    Sushanta Kumar Mishra, Scott Evan Millman, Lingbo Zhang.
      Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemia cells is often genotype-specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML, explores the role of key vitamins and enzymes that regulate these processes, and provides an overview of metabolism-directed therapies currently in use or development.
    DOI:  https://doi.org/10.1182/blood.2022018092
  5. Leuk Res. 2022 Dec 16. pii: S0145-2126(22)00378-2. [Epub ahead of print]124 107002
    Molecular genetic characterization of Philadelphia chromosome-positive acute myeloid leukemia.
    Qianghua Zhou, Davidson Zhao, Entsar Eladl, Jose-Mario Capo-Chichi, Dennis Dong Hwan Kim, Hong Chang.
       BACKGROUND: Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) is a provisional disease entity in the 2016 WHO classification, while its genetic profile of Ph+ AML remains poorly defined. In addition, the differentiating features of Ph+ AML and chronic myeloid leukemia in myeloid blast crisis (CML-MBC) remain controversial.
    METHODS: We conducted a retrospective study of 15 Ph+ AML patients to compare their clinical and laboratory profiles with 27 CML-MBC patients.
    RESULTS: Compared to CML-MBC, Ph+ AML patients presented with significantly higher peripheral WBC count and bone marrow blast percentage. The immunophenotypic profiles were largely similar between Ph+ AML and CML-MBC, except for CD4 expression, which was significantly enriched in CML-MBC. Ph+ AML patients less frequently harboured co-occurring additional cytogenetic abnormalities (ACA) compared to CML-MBC, and trisomy 19 (23%) and IDH1/2 (46%) were the most common ACA and mutated genes in Ph+ AML, respectively. Overall survival (OS) did not significantly differ between Ph+ AML and CML-MBC. Ph+ AML without CML-like features appeared to have a better outcome compared to Ph+ AML with CML-like features; ACA in Ph+ AML may confer an even worse prognosis.
    CONCLUSIONS: Our results indicate that patients with Ph+ AML share similar genetic profiles and clinical outcomes with those with CML-MBC, thus should be classified as a high-risk entity.
    Keywords:  Clinical outcomes; Molecular cytogenetics; NGS; Ph+ AML
    DOI:  https://doi.org/10.1016/j.leukres.2022.107002
  6. Blood. 2022 Dec 21. pii: blood.2022016929. [Epub ahead of print]
    The tetraspanin CD53 protects stressed hematopoietic stem cells via promotion of DREAM complex- mediated quiescence.
    Zev J Greenberg, Darlene Monlish, Luana Chiquetto Paracatu, Qian Dong, Michael P Rettig, Nate Dee Roundy, Rofaida Gaballa, Weikai Li, Wei Yang, Cliff J Luke, Laura Schuettpelz.
      Hematopoietic stem cells (HSCs) cycle in response to inflammatory and other proliferative stressors; however, they must quickly return to quiescence to avoid exhaustion and maintain their functional integrity. The mechanisms that regulate this return to quiescence are not well understood. Here we show that the tetraspanin CD53 is markedly upregulated in HSCs in response to a variety of inflammatory and proliferative stimuli, and loss of CD53 is associated with prolonged cycling and reduced HSC function in the context of inflammatory stress. Mechanistically, CD53 promotes the activity of the DREAM transcriptional repressor complex, which downregulates genes associated with cycling and division. Proximity labeling and confocal fluorescent microscopy studies show that CD53 interacts with DREAM-associated proteins, specifically promoting the interaction between Rbl2/p130 and its phosphatase, PP2A, effectively stabilizing p130 protein availability for DREAM binding. Together, these data identify a novel mechanism by which stressed HSCs resist continued cycling.
    DOI:  https://doi.org/10.1182/blood.2022016929
  7. Blood Cancer J. 2022 12 19. 12(12): 170
    Prognostic impact of the AML ELN2022 risk classification in patients undergoing allogeneic stem cell transplantation.
    Madlen Jentzsch, Lara Bischof, Jule Ussmann, Donata Backhaus, Dominic Brauer, Klaus H Metzeler, Maximilian Merz, Vladan Vucinic, Georg-Nikolaus Franke, Marco Herling, Uwe Platzbecker, Sebastian Schwind.
      For most patients with acute myeloid leukemia (AML), an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the diagnosis and risk classification in AML based on genetic factors at diagnosis as well as a dynamic adjustment (reclassification) according to the measurable residual disease (MRD) status for the favorable and intermediate risk groups. Validation of the ELN2022 risk classification has not been reported. We retrospectively analyzed 522 AML patients who received an HSCT at a median age of 59 (range 16-76) years. For patients with adequate material available and in remission prior to HSCT (n = 229), the MRD status was evaluated. Median follow-up after HSCT was 3.0 years. ELN2022 risk at diagnosis was in 22% favorable, in 26% intermediate, and in 52% adverse. ELN2022 risk at diagnosis is associated with the cumulative incidence of relapse/progression (CIR), event-free survival (EFS), and overall survival (OS) in the whole patient cohort, as well as the subgroup of patients transplanted in first remission. However, the risk stratification based on the ELN2022 classification did not significantly improve outcome prognostication in comparison to the ELN2017 classification. In our study, the newly added group of patients with myelodysplasia-related gene mutations did not have adverse outcomes. Re-classifying these patients into the intermediate risk group and adjusting the grouping for all AML patients by MRD at HSCT, led to a refined and improved risk stratification, which should be validated in independent studies.
    DOI:  https://doi.org/10.1038/s41408-022-00764-9
  8. Am J Hematol. 2022 Dec 24.
    Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G-CSF based regimens.
    Jayastu Senapati, Tareq Abuasab, Fadi G Haddad, Farhad Ravandi, Tapan Kadia, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Yesid Alvarado, Mark A Brandt, Hagop Kantarjian, Gautam Borthakur.
      
    DOI:  https://doi.org/10.1002/ajh.26811
  9. Leuk Res. 2022 Dec 14. pii: S0145-2126(22)00375-7. [Epub ahead of print]124 106999
    Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome: A large single institution analysis of 1774 patients.
    Somedeb Ball, Luis E Aguirre, Akriti G Jain, Najla Al Ali, Sara M Tinsley, Onyee Chan, Andrew T Kuykendall, Kendra Sweet, Jeffrey E Lancet, David A Sallman, Mohammad Omar Hussaini, Eric Padron, Rami S Komrokji.
      EZH2 mutations in myeloid neoplasms are loss of function type, and have been linked to poor overall survival (OS) in patients with myelodysplastic syndrome (MDS). However, the specific determinants of outcomes in EZH2-mutant (mut) MDS are not well characterized. In this single-center retrospective study, clinical and genomic data were collected on 1774 patients with MDS treated at Moffitt Cancer Center. In our cohort, 83 (4.7%) patients had a pathogenic EZH2 mutation. Patients with EZH2mut MDS were older than EZH2-wild type (wt) group (median age- 72 vs. 69 years, p = 0.010). The most common co-occurring mutation in EZH2mut MDS was ASXL1, with a significantly higher frequency than EZH2wt (54% vs. 19%, p < 0.001). Patients with EZH2mut MDS had lower response rates to hypomethylating agents compared to EZH2wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2mut MDS was 30.8 months, with a significantly worse OS than EZH2wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2mut MDS, co-presence of ASXL1 or RUNX1 mutations was associated with inferior median OS compared to their wt counterparts (26.8 vs. 48.7 months, p = 0.031). Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.
    Keywords:  ASXL1; Deletion 7q; EZH2; Hypomethylating agent; Overall survival; RUNX1
    DOI:  https://doi.org/10.1016/j.leukres.2022.106999
  10. Oncotarget. 2022 Dec 20. 13 1359-1368
    Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model.
    Hirofumi Tsuzuki, Tatsuya Kawase, Taisuke Nakazawa, Masamichi Mori, Taku Yoshida.
      Antibody drug conjugates (ADC) are one of the attractive modalities for the treatment of acute myeloid leukemia (AML). Previously, we have developed ASP1235, a novel ADC targeting Fms-like tyrosine kinase 3 (FLT3) which is widely expressed on the leukemic blasts of AML patients. In this study, we sought to evaluate the therapeutic effect of ASP1235 in combination with venetoclax plus azacitidine, a novel standard-of-care treatment for elderly AML patients, in ASP1235 poor sensitive AML cells. To identify the suitable preclinical model, we first evaluated the growth inhibitory effect of ASP1235 on several leukemia cell lines expressing FLT3 and found that THP-1 cells were partially sensitive to ASP1235 in vitro. Furthermore, ASP1235 showed marginal anti-tumor activity in a THP-1 xenograft model. Compared to the leukemic blasts in most of the relapsed or refractory (R/R) AML patients tested, THP-1 cells expressed equivalent protein levels of Bcl-2, suggesting that ASP1235 in combination with venetoclax plus azacitidine is a rational treatment in the THP-1 model. In vitro, ASP1235 showed a cytotoxic effect on THP-1 cells in combination with venetoclax, and the combination effect was greater than the additive effect. Furthermore, ASP1235 also showed a combination effect with venetoclax plus azacitidine treatment. Similarly, the combination of ASP1235, venetoclax and azacitidine showed a superior anti-tumor effect in a THP-1 xenograft model without obvious body weight loss. These findings provide supportive evidence that the triple combination of ASP1235, venetoclax and azacitidine would improve the clinical outcome of ASP1235 monotherapy and venetoclax plus azacitidine regimen in AML patients.
    Keywords:  ASP1235; acute myeloid leukemia (AML); antibody drug conjugate (ADC); azacitidine; venetoclax
    DOI:  https://doi.org/10.18632/oncotarget.28331
  11. Cancer Cell. 2022 Dec 17. pii: S1535-6108(22)00588-8. [Epub ahead of print]
    Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.
    Eric Wang, Jose Mario Bello Pineda, Won Jun Kim, Sisi Chen, Jessie Bourcier, Maximilian Stahl, Simon J Hogg, Jan Phillipp Bewersdorf, Cuijuan Han, Michael E Singer, Daniel Cui, Caroline E Erickson, Steven M Tittley, Alexander V Penson, Katherine Knorr, Robert F Stanley, Jahan Rahman, Gnana Krishnamoorthy, James A Fagin, Emily Creger, Elizabeth McMillan, Chi-Ching Mak, Matthew Jarvis, Carine Bossard, Darrin M Beaupre, Robert K Bradley, Omar Abdel-Wahab.
      Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.
    Keywords:  BCL2; CLK; DYRK; RBM10; RNA splicing; XIAP; acute myeloid leukemia; venetoclax
    DOI:  https://doi.org/10.1016/j.ccell.2022.12.002
  12. Front Cell Infect Microbiol. 2022 ;12 1012334
    High rate of invasive fungal infections during early cycles of azacitidine for patients with acute myeloid leukemia.
    Sing-Ting Wang, Chia-Huei Chou, Tzu-Ting Chen, Ching-Chan Lin, Li-Yuan Bai, Shih-Peng Yeh, Mao-Wang Ho, Ming-Yu Lien.
       Background: Acute myeloid leukemia (AML) is a form of cancer that is characterized by infiltration of the bone marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally poorly differentiated cells of the hematopoietic system. Patients with acute myeloid leukemia (AML) receiving azacitidine (AZA) alone or in combination with venetoclax (VEN-AZA) are at increased risk for invasive fungal infections (IFIs). We compared the incidence and risk of IFI during these treatment regimens in a single Taiwan hospital.
    Materials and methods: A total of 61 patients with AML received at least one course of AZA in the hematology ward of China Medical University Hospital (Taichung, Taiwan) between September 2012 and June 2020. Thirty-eight patients (62.3%) received AZA monotherapy; 23 (37.7%) received VEN-AZA.
    Results: Incidence rates of probable and proven IFI were 18% and 1.6%, respectively, during AZA treatment. One proven case of Fusarium spp. infection was isolated by skin and soft tissue culture. Most (75%) IFI cases occurred during the first cycle of AZA therapy. Half of all IFI cases occurred in patients with prolonged neutropenia. The risk of IFI was significantly higher for the European LeukemiaNet (ELN) nonfavorable-risk group (intermediate- and adverse-risk group) versus the ELN favorable-risk group and for patients with prolonged neutropenia versus those without (P<0.05 for both comparisons). In this study, median OS did not differ significantly between patients with and without IFIs during AZA-containing regimens (14.6 months vs 13.7 months; P=0.59).
    Conclusion: The incidence of IFI was high in this AML cohort treated with AZA-containing regiments in Taiwan. The majority of IFI cases occurred during the early cycles of AZA (cycles 1-2). Prospective studies are needed to determine the optimal choice of antifungal prophylaxis agent during VEN-AZA therapy for AML.
    Keywords:  Taiwan hospital; acute myeloid leukemia; azacitidine; invasive fungal infection; venetoclax and azacitidine
    DOI:  https://doi.org/10.3389/fcimb.2022.1012334
  13. Clin Cancer Res. 2022 Dec 19. pii: CCR-22-2540. [Epub ahead of print]
    Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates.
    Evan C Chen, Helen Gandler, Isidora Tošić, Geoffrey G Fell, Ashlee Fiore, Olga Pozdnyakova, Daniel J DeAngelo, Ilene Galinsky, Marlise R Luskin, Martha S Wadleigh, Eric S Winer, Rebecca Leonard, Kelsey O'Day, Adrienne de Jonge, Donna Neuberg, A Thomas Look, Richard M Stone, David A Frank, Jacqueline S Garcia.
       PURPOSE: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the fibroblast growth factor receptor (FGFR) pathway is a common mechanism of resistance.
    PATIENTS AND METHODS: We performed preclinical studies followed by a phase 1 trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted.
    RESULTS: The primary DLT observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in two of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. While the maximum tolerated dose of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.
    CONCLUSIONS: We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2540
  14. Blood Cancer J. 2022 12 19. 12(12): 169
    Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis.
    Daehun Kwag, Byung-Sik Cho, Su-Yeon Bang, Jong Hyuk Lee, Gi-June Min, Sung-Soo Park, Silvia Park, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong Wook Lee, Hee-Je Kim.
      Venetoclax (VEN) combined with azacitidine (AZA) or decitabine (DEC) has been approved for older adults with acute myeloid leukemia (AML) unfit for intensive chemotherapy based on the pivotal VIALE-A trial. However, this trial only compared AZA + VEN with AZA monotherapy. Therefore, we compared the outcomes of consecutive older adults (65 years or older) with newly diagnosed AML who received DEC (n = 230) or DEC + VEN (n = 74) after propensity score matching to construct a one-to-one matched cohort by the nearest neighbor algorithm. The median overall survival was longer in the DEC + VEN group than in the DEC group (13.4 months vs. 8.3 months, p = 0.01). The median event-free survivals were 8.6 and 5.8 months in the DEC + VEN and DEC groups, respectively (p = 0.02). The response rate (complete response, complete response with incomplete hematologic recovery, and morphologic leukemia-free state) was significantly higher in the DEC + VEN group than in the DEC group (70.3% vs. 24.3%, p < 0.01). The 30-day (2.7% vs. 9.5%, p = 0.17) and 60-day (9.5% vs. 18.9%, p = 0.16) mortality rates did not differ between the two groups, nor did the median hospitalization and transfusion rates (hospitalization: 23 days vs. 21 days, p = 0.20; red blood cells: 3.2 units/month vs. 3.5 units/month, p = 0.73; platelets: 2.7 units/month vs. 2.3 units/months, p = 0.48). Of those who received DEC + VEN and became leukemia-free, 29% underwent allogeneic stem cell transplantation and had excellent survival outcomes (one-year survival: 79.4%; one-year non-relapse mortality: 13.3%). This study is the first to provide real-world evidence that DEC + VEN has superior outcomes to DEC monotherapy.
    DOI:  https://doi.org/10.1038/s41408-022-00770-x
  15. Nat Methods. 2022 Dec 22.
    Efficient combinatorial targeting of RNA transcripts in single cells with Cas13 RNA Perturb-seq.
    Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Yuhan Hao, Efthymia Papalexi, William M Mauck, Lu Lu, John A Morris, Eleni P Mimitou, Peter Smibert, Neville E Sanjana, Rahul Satija.
      Pooled CRISPR screens coupled with single-cell RNA-sequencing have enabled systematic interrogation of gene function and regulatory networks. Here, we introduce Cas13 RNA Perturb-seq (CaRPool-seq), which leverages the RNA-targeting CRISPR-Cas13d system and enables efficient combinatorial perturbations alongside multimodal single-cell profiling. CaRPool-seq encodes multiple perturbations on a cleavable CRISPR array that is associated with a detectable barcode sequence, allowing for the simultaneous targeting of multiple genes. We compared CaRPool-seq to existing Cas9-based methods, highlighting its unique strength to efficiently profile combinatorially perturbed cells. Finally, we apply CaRPool-seq to perform multiplexed combinatorial perturbations of myeloid differentiation regulators in an acute myeloid leukemia (AML) model system and identify extensive interactions between different chromatin regulators that can enhance or suppress AML differentiation phenotypes.
    DOI:  https://doi.org/10.1038/s41592-022-01705-x
  16. Int J Mol Sci. 2022 Dec 14. pii: 15907. [Epub ahead of print]23(24):
    The Latest Breakthroughs in Immunotherapy for Acute Myeloid Leukemia, with a Special Focus on NKG2D Ligands.
    Stefanie Maurer, Xiaoxuan Zhong, Betsy Deza Prada, John Mascarenhas, Lucas Ferrari de Andrade.
      Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been substantial progress in the developments of immunotherapeutic approaches for AML over the last several years, including the development of antibodies that further increase the innate immunogenicity of leukemia cells by the inhibition of NKG2D ligand-particularly MICA and MICB-shedding, chimeric proteins such as IL-15 superagonist that expand natural killer (NK) cells, blockers of immunologic checkpoints such as NKG2A, and chemicals that indirectly increase expression of immune stimulatory proteins in leukemia stem cells. Furthermore, cellular therapies have been designed to enable alloreactive immunity by allogeneic NK cells or target leukemia antigens such as mutated NPM1. These immunotherapeutic approaches have demonstrated remarkable efficacies in preclinical studies and have successfully transitioned to early phase clinical trials, to establish safety and initial signal of clinical activity. Here, we briefly discuss some of the most recent and impactful developments in the AML immunotherapy field and provide our perspectives for the future directions of this exciting and new therapeutic opportunity.
    Keywords:  AML; NK cells; antibodies; immunotherapy
    DOI:  https://doi.org/10.3390/ijms232415907
  17. J Immunother Cancer. 2022 Dec;pii: e004794. [Epub ahead of print]10(12):
    TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis.
    Franziska Brauneck, Brit Fischer, Marius Witt, Jana Muschhammer, Jennyfer Oelrich, Pedro Henrique da Costa Avelar, Sophia Tsoka, Lars Bullinger, Elisa Seubert, Daniel J Smit, Carsten Bokemeyer, Christin Ackermann, Jasmin Wellbrock, Friedrich Haag, Walter Fiedler.
       BACKGROUND: Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).
    METHODS: The phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro.
    RESULTS: In pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT+ M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells.
    CONCLUSION: Our findings suggest that immunosuppressive TIGIT+ M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future.
    Keywords:  Costimulatory and Inhibitory T-Cell Receptors; Hematologic Neoplasms; Macrophages; Metabolic Networks and Pathways; Tumor Escape
    DOI:  https://doi.org/10.1136/jitc-2022-004794
  18. Br J Haematol. 2022 Dec 23.
    Cord blood versus haploidentical transplantations for non-remission acute myeloid leukaemia: Authors' reply.
    Kensuke Matsuda, Takaaki Konuma, Masamitsu Yanada.
      
    DOI:  https://doi.org/10.1111/bjh.18626
  19. Hematol Oncol Stem Cell Ther. 2022 Dec 15. 15(3): 131-136
    Chimeric Antigen Receptor T-cell Therapy for Acute Myeloid Leukemia.
    Xia Bi, Jingmei Hsu, Mia Gergis, Yang Yang, Dongni Yi, Usama Gergis.
      Chimeric antigen receptor (CAR) T-cells targeting CD19 have drastically improved the outcomes of B-cell malignancies; however, the success has not yet extended to myeloid malignancies such as acute myeloid leukemia (AML). Main impediments in the development of CAR T therapy in AML include difficulty in identifying appropriate target antigens that are specific to myeloid leukemia stem cells while sparing the healthy hematopoietic stem progenitor cells (HSPCs). Herein, we discuss the current state of CAR T-cell therapy in AML, highlighting recent progress and limitations in clinical translation. We also discuss novel approaches in CAR T therapy development and potential strategies to enhance anti-leukemic activity while minimizing toxicity to heathy cells to make CAR T-cell therapy a viable option for patients with AML.
    DOI:  https://doi.org/10.56875/2589-0646.1062
  20. Blood. 2022 Dec 21. pii: blood.2022017739. [Epub ahead of print]
    Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances.
    Christopher R Reilly, Akiko Shimamura.
      Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosome maturation due to deficiency of SBDS and inability to evict the anti-association factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for SDS patients who develop myeloid malignancies are extremely poor due to high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for SDS patients who undergo routine bone marrow surveillance and receive a HSCT prior to developing overt malignancy. However, the optimal approach to hematologic surveillance and timing of HSCT for SDS patients is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in SDS patients that either alleviate the ribosome defect by somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in SDS patients have biallelic loss-of-function TP53 mutations. Single cell DNA sequencing (scDNA-seq) of SDS bone marrow samples can detect pre-malignant biallelic TP53-mutated clones prior to clinical diagnosis, suggesting molecular surveillance may enhance detection of incipient myeloid malignancies when HSCT may be most effective. Here we review the clinical, genetic, and biologic features of SDS. Additionally, we present evidence supporting hematologic surveillance for SDS patients that incorporates clinical, pathologic, and molecular data to risk-stratify patients and prioritize transplant evaluation for SDS patients with high-risk features.
    DOI:  https://doi.org/10.1182/blood.2022017739
  21. Blood Rev. 2022 Dec 01. pii: S0268-960X(22)00110-2. [Epub ahead of print] 101036
    Acute myeloid leukemia resistant to venetoclax-based therapy: What does the future hold?
    Prajwal Dhakal, Melissa Bates, Michael H Tomasson, Grerk Sutamtewagul, Adam Dupuy, Vijaya Raj Bhatt.
      Venetoclax is a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, which, combined with a DNA hypomethylating agent or low dose cytarabine, results in high rates of initial responses in patients with acute myeloid leukemia (AML). However, the disease relapses in most patients. Mechanisms of resistance to venetoclax-based therapy include TP53 gene mutations or inactivation of p53 protein, activating kinase mutations such as FLT3 and RAS, and upregulation of other BCL-2 family apoptotic proteins. Current clinical trials are exploring strategies such as doublet or triplet regimens incorporating a p53 activator, an anti-CD47 antibody, or other novel agents that target genes and proteins responsible for resistance to venetoclax. Further studies should focus on identifying predictive biomarkers of response to venetoclax-based therapy and incorporating immunotherapeutic approaches such as checkpoint inhibitors, bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy to improve outcomes for patients with AML.
    Keywords:  Acute myeloid leukemia; Apoptosis; FLT3; Mutations; TP53; Venetoclax, resistance
    DOI:  https://doi.org/10.1016/j.blre.2022.101036
  22. Cancers (Basel). 2022 Dec 12. pii: 6121. [Epub ahead of print]14(24):
    FLT3-ITD Measurable Residual Disease Monitoring in Acute Myeloid Leukemia Using Next-Generation Sequencing.
    Jong-Mi Lee, Silvia Park, Insik Hwang, Dain Kang, Byung Sik Cho, Hee-Je Kim, Ari Ahn, Myungshin Kim, Yonggoo Kim.
      The in-frame internal tandem duplication (ITD) of the FMS-like tyrosine kinase 3 (FLT3) gene is an important negative prognostic marker in acute myeloid leukemia (AML). FLT3-ITD monitoring is essential for patients at relapse or those receiving FLT3-targeted therapies. Fragment analysis (FA) is commonly used to detect and quantify FLT3-ITDs; however, detecting low-burden FLT3-ITDs after a treatment is challenging. We, therefore, developed a customized, next-generation sequencing (NGS)-based FLT3-ITD assay that includes a new ITD-tracing algorithm, "SEED", optimized for measurable residual disease (MRD) monitoring. NGS-SEED showed an enhanced sensitivity (0.001%) and has a superior performance over conventional fragment analysis. We further investigated the prognostic impact of MRD analyzed by NGS-SEED in AML patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Our assay showed that the MRD assessed before and after HSCT were significantly associated with a risk of relapse and a poor overall survival, respectively, in a time-dependent analysis. Thus, this report highlighted the prognostic value of serial MRD monitoring using a sensitive method in a clinical setting of AML patients with FLT3-ITD.
    Keywords:  FLT3-ITD; acute myeloid leukemia; bone marrow transplantation; hematopoietic stem cell transplantation; measurable residual disease; next generation sequencing
    DOI:  https://doi.org/10.3390/cancers14246121
  23. Blood. 2022 Dec 19. pii: blood.2022017416. [Epub ahead of print]
    Biology and therapeutic targeting of molecular mechanisms in MPN.
    Joan How, Jacqueline S Garcia, Ann Mullally.
      Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. As a result, JAK inhibitors have been the standard therapy to treat myelofibrosis (MF) patients. Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia (ET) and polycythemia vera (PV), treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications, but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis, and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin and the inflammatory bone marrow microenvironment.
    DOI:  https://doi.org/10.1182/blood.2022017416
  24. Clin Cancer Res. 2022 Dec 20. pii: CCR-22-1763. [Epub ahead of print]
    Crizotinib has Preclinical Efficacy in Philadelphia-negative Myeloproliferative Neoplasms.
    Lindsay M Gurska, Rachel Okabe, Alexandra Schurer, Meng Maxine Tong, Mark Soto, Daniel Choi, Kristina Ames, Shira Glushakow-Smith, Allison Montoya, Ellen Tein, Linde A Miles, Haiying Cheng, Pamela Giblin, Ross L Levine, Swati Goel, Balazs Halmos, Kira Gritsman.
       PURPOSE: The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation.
    EXPERIMENTAL DESIGN: Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non-small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation.
    RESULTS: We found that crizotinib suppresses proliferation and activation of JAK2/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN.
    CONCLUSIONS: In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of MPN patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1763
  25. Clin Cancer Res. 2022 Dec 22. pii: CCR-22-2628. [Epub ahead of print]
    Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia.
    Kendra L Sweet, Jorge E Cortes, Jane F Apperley, Mel Mann, Michael J Mauro, Vivian G Oehler, Cristina Ruiz, Charles A Schiffer, Lori A Ehrlich, Gulsum E Pamuk, Joseph Wynne, Gautam U Mehta, R Angelo de Claro, Marc R Theoret, B Douglas Smith, Kelly J Norsworthy.
      The Food and Drug Administration (FDA) has an accelerated approval program for drugs which have been identified as promising treatments for serious conditions when the available data suggests that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here a group of academic CML experts, patient panelists and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2628
  26. Leukemia. 2022 Dec 21.
    Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.
    Evan M Braunstein, Eddie Imada, Sergiu Pasca, Shiyu Wang, Hang Chen, Camille Alba, Dan N Hupalo, Matthew Wilkerson, Clifton L Dalgard, Jack Ghannam, Yujia Liu, Luigi Marchionni, Alison Moliterno, Christopher S Hourigan, Lukasz P Gondek.
      Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.
    DOI:  https://doi.org/10.1038/s41375-022-01797-6
  27. Nat Metab. 2022 Dec;4(12): 1792-1811
    mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.
    Aaron M Hosios, Meghan E Wilkinson, Molly C McNamara, Krystle C Kalafut, Margaret E Torrence, John M Asara, Brendan D Manning.
      The mechanistic target of rapamycin complex 1 (mTORC1) senses and relays environmental signals from growth factors and nutrients to metabolic networks and adaptive cellular systems to control the synthesis and breakdown of macromolecules; however, beyond inducing de novo lipid synthesis, the role of mTORC1 in controlling cellular lipid content remains poorly understood. Here we show that inhibition of mTORC1 via small molecule inhibitors or nutrient deprivation leads to the accumulation of intracellular triglycerides in both cultured cells and a mouse tumor model. The elevated triglyceride pool following mTORC1 inhibition stems from the lysosome-dependent, but autophagy-independent, hydrolysis of phospholipid fatty acids. The liberated fatty acids are available for either triglyceride synthesis or β-oxidation. Distinct from the established role of mTORC1 activation in promoting de novo lipid synthesis, our data indicate that mTORC1 inhibition triggers membrane phospholipid trafficking to the lysosome for catabolism and an adaptive shift in the use of constituent fatty acids for storage or energy production.
    DOI:  https://doi.org/10.1038/s42255-022-00706-6
  28. Exp Hematol. 2022 Dec 16. pii: S0301-472X(22)00838-4. [Epub ahead of print]
    miR-495-3p Sensitizes BCR-ABL1 Expressing Leukemic cells to Tyrosine Kinase Inhibitors by Targeting Multidrug Resistance 1 Gene including in T315I Mutated cells.
    Yutthana Rittavee, Jérôme Artus, Christophe Desterke, Isidora Simanic, Lucas Eduardo Botelho de Souza, Sandra Riccaldi, Sabrina Coignard, Yousef Ijjeh, Patricia Hugues, Annelise Bennaceur-Griscelli, Ali G Turhan, Adlen Foudi.
      Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy driven by the BCR-ABL1 fusion oncoprotein. The development of tyrosine kinase inhibitors (TKIs) has deeply increased long-term survival of CML patients. Nonetheless, one patient out of four will switch TKI off owing either to drug intolerance or resistance partly due to amplification or mutations of BCR-ABL1 oncogene and alteration of ATP-binding cassette (ABC) transporters. Increasing evidence suggests an involvement of the microRNA miR-495-3p in cancer-associated chemo-resistance through multidrug resistance 1 (MDR1) gene which encodes an ATP-dependent efflux pump. Our study aimed at investigating the potential role of miR-495-3p in CML TKI chemo-sensitivity and determining the underlying molecular circuitry involved. We first observed that miR-495-3p expression was lower in BCR-ABL1 expressing cellular models in vitro. Notably, loss-of-function experiments showed increased proliferation associated with a decreased number of non-dividing cells (G0/G1) and resistance to Imatinib. Conversely, our data showed that miR-495-3p overexpression hindered leukemic cell growth and TKI resistance even in Imatinib-resistant T315I-mutant cells as well as drug efflux activity through MDR1 regulation. To further investigate the role of miR-495-3p in CML patients, we found that predicted miR-495-3p targets were upregulated in patients in blast crisis involved in protein phosphorylation and associated with the worst prognosis. Taken together, our results demonstrate that down-regulation of miR-495-3p expression is important in the malignant phenotype of CML and TKI resistance mechanisms, which could be a useful biomarker and a potential therapeutic target to eradicate CML.
    Keywords:  ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects; ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*; Blast Crisis / pathology; Cell Line, Tumor; Cell Proliferation / drug effects*; Cell Survival / drug effects; Drug Resistance; Genes, MDR; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MicroRNAs / genetics; MicroRNAs / physiology*
    DOI:  https://doi.org/10.1016/j.exphem.2022.12.003
  29. JCO Clin Cancer Inform. 2022 Dec;6 e2200044
    Predicting In-Hospital Mortality After Acute Myeloid Leukemia Therapy: Through Supervised Machine Learning Algorithms.
    Nauman S Siddiqui, Andreas Klein, Amandeep Godara, Rachel J Buchsbaum, Michael C Hughes.
       PURPOSE: Despite careful patient selection, induction chemotherapy for acute myeloid leukemia (AML) is associated with a considerable risk for treatment-related mortality (5%-20%). We evaluated machine learning (ML) algorithms trained using factors available at the time of admission for AML therapy to predict death during the hospitalization.
    METHODS: We included AML discharges with age > 17 years who received inpatient chemotherapy from State Inpatient Database from Arizona, Florida, New York, Maryland, Washington, and New Jersey for years 2008-2014. The primary objective was to predict inpatient mortality in patients undergoing chemotherapy using covariates present before initiation of chemotherapy. ML algorithms logistic regression (LR), decision tree, and random forest were compared.
    RESULTS: 29,613 hospitalizations for patients with AML were included in the analysis each with 4,177 features. The median age was 58.9 (18-101) years, 13,689 (53.7%) were male, and 20,203 (69%) were White. The mean time from admission to chemotherapy was 3 days (95% CI, 2.9 to 3.1), and 2,682 (9.1%) died during the hospitalization. Both LR and random forest models achieved an area under the curve (AUC) score of 0.78, whereas decision tree achieved an AUC of 0.70. The baseline LR model with age yielded an AUC of 0.62. To clinically balance and minimize false positives, we selected a decision threshold of 0.7 and at this threshold, 51 of our test set of 5,923 could have potentially averted treatment-related mortality.
    CONCLUSION: Using readily accessible variables, inpatient mortality of patients on track for chemotherapy to treat AML can be predicted through ML algorithms. The model also predicted inpatient mortality when tested on different data representations and paves the way for future research.
    DOI:  https://doi.org/10.1200/CCI.22.00044
  30. Sci Rep. 2022 Dec 17. 12(1): 21832
    Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis.
    Yuhan Yan, Chao Chen, Zhiguo Li, Jing Zhang, Narin Park, Cheng-Kui Qu.
      Amino acid-mediated metabolism is one of the key catabolic and anabolic processes involved in diverse cellular functions. However, the role of the semi-essential amino acid arginine in normal and malignant hematopoietic cell development is poorly understood. Here we report that a continuous supply of exogenous arginine is required for the maintenance/function of normal hematopoietic stem cells (HSCs). Surprisingly, knockout of Slc7a3 (CAT3), a major L-arginine transporter, does not affect HSCs in steady-state or under stress. Although Slc7a3 is highly expressed in naïve and activated CD8 T cells, neither T cell development nor activation/proliferation is impacted by Slc7a3 depletion. Furthermore, the Slc7a3 deletion does not attenuate leukemia development driven by Pten loss or the oncogenic Ptpn11E76K mutation. Arginine uptake assays reveal that L-arginine uptake is not disrupted in Slc7a3 knockout cells. These data suggest that extracellular arginine is critically important for HSCs, but CAT3 is dispensable for normal hematopoiesis and leukemogenesis.
    DOI:  https://doi.org/10.1038/s41598-022-24554-2
  31. Leukemia. 2022 Dec 22.
    Retrospective analysis of hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: conditioning intensity matters.
    Peter-Martin Bruch, Sascha Dietrich, Herve Finel, Ariane Boumendil, Hildegard Greinix, Thomas Heinicke, Wolfgang Bethge, Dietrich Beelen, Christoph Schmid, Hans Martin, Luca Castagna, Christof Scheid, Kerstin Schäfer-Eckart, Jörg Bittenbring, Jürgen Finke, Henrik Sengeloev, Mael Heiblig, Jan Cornelissen, Patrice Chevallier, Mohamad Mohty, Stephen Robinson, Silvia Montoto, Peter Dreger.
      Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20-73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.
    DOI:  https://doi.org/10.1038/s41375-022-01782-z
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