bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–08–28
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.
  2. Lipids and the cancer stemness regulatory system in acute myeloid leukemia.
  3. Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations.
  4. Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
  5. Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm.
  6. Current status and future perspectives in targeted therapy of NPM1-mutated AML.
  7. Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia.
  8. Outcomes in Patients With Poor-risk Cytogenetics With or Without TP53 Mutations Treated With Venetoclax and Azacitidine.
  9. EGR1 haploinsufficiency confers a fitness advantage to hematopoietic stem cells following chemotherapy.
  10. The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation.
  11. Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias.
  12. Impact of emerging ACA on survival in chronic myeloid leukemia (CML).
  13. Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition.
  14. Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.
  15. An open-label, phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858, an unconjugated anti-CD33 monoclonal antibody, in combination with decitabine in patients with acute myeloid leukemia.
  16. NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition.
  17. Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives.
  18. A tubulin binding molecule drives differentiation of acute myeloid leukemia cells.
  19. Mutant SF3B1 splices a more leukemogenic EVI1.
  20. CHIPing away the progression potential of CHIP: A new reality in the making.
  21. DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells.
  22. Management of older patients with frailty and acute myeloid leukaemia: A British Society for Haematology good practice paper.
  23. Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS.
  24. Longitudinal metabolic study of red blood cells from patients undergoing gender-affirming testosterone therapy.
  25. Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications.
  26. ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.
  27. Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study.
  28. Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.
  29. Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34+  hematopoietic stem and progenitor cells.
  30. Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.
  31. Cancer vaccines: the next immunotherapy frontier.
  32. FLT3-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia.
  33. Ubiquitin E3 ligase FBXO21 regulates cytokine mediated signaling pathways, but is dispensable for steady-state hematopoiesis.
  34. Identifying mutant-specific multi-drug combinations using comparative network reconstruction.
  35. N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
  36. DAXX-ATRX regulation of p53 chromatin binding and DNA damage response.
  1. Leukemia. 2022 Aug 23.
    Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.
    Sebastian E Koschade, Kevin Klann, Shabnam Shaid, Binje Vick, Jan A Stratmann, Marlyn Thölken, Laura M Meyer, The Duy Nguyen, Julia Campe, Laura M Moser, Susanna Hock, Fatima Baker, Christian T Meyer, Frank Wempe, Hubert Serve, Evelyn Ullrich, Irmela Jeremias, Christian Münch, Christian H Brandts.
      Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically investigated acute cellular responses to on-target therapy with multiple FLT3i in FLT3-ITD + AML using recently developed functional translatome proteomics (measuring changes in the nascent proteome) with phosphoproteomics. This pinpointed AKT-mTORC1-ULK1-dependent autophagy as a dominant resistance mechanism to on-target FLT3i therapy. FLT3i induced autophagy in a concentration- and time-dependent manner specifically in FLT3-ITD + cells in vitro and in primary human AML cells ex vivo. Pharmacological or genetic inhibition of autophagy increased the sensitivity to FLT3-targeted therapy in cell lines, patient-derived xenografts and primary AML cells ex vivo. In mice xenografted with FLT3-ITD + AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.
    DOI:  https://doi.org/10.1038/s41375-022-01678-y
  2. Essays Biochem. 2022 Aug 23. pii: EBC20220028. [Epub ahead of print]
    Lipids and the cancer stemness regulatory system in acute myeloid leukemia.
    Isabel N X Lim, Murtaza S Nagree, Stephanie Z Xie.
      Acute myeloid leukemia (AML) is a heterogeneous disease of impaired myeloid differentiation and a caricature of normal hematopoiesis. Leukemic stem cells (LSCs) are responsible for long-term clonal propagation in AML just as hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis. LSCs are often resistant to standard chemotherapy and are responsible for clinical relapse. Although AML is highly heterogeneous, determinants of stemness are prognostic for AML patient survival and can predict AML drug sensitivity. Therefore, one way to overcome challenges preventing efficacious treatment outcomes is to target LSC stemness. Metabolomic and lipidomic studies of serum and cells from AML patients are emerging to complement genomic, transcriptomic, epigenetic, and proteomic data sets to characterize and stratify AML. Recent studies have shown the value of fractionating LSCs versus blasts when characterizing metabolic pathways and implicate the importance of lipid balance to LSCs function. As more extensive metabolic studies coupled to functional in vivo assays are conducted on highly purified HSCs, bulk AML, and LSCs, the similarities and differences in lipid homeostasis in stem-like versus more mature AML subtypes as well as from normal HSCs are emerging. Here, we discuss the latest findings from studies of lipid function in LSCs, with a focus on sphingolipids (SLs) as stemness/lineage fate mediators in AML, and the balance of fatty acid anabolism and catabolism fueling metabolic flexibility and drug resistance in AML. We also discuss how designing successful strategies to target lipid vulnerabilities and improve AML patient survival should take into consideration the hierarchical nature of AML.
    Keywords:  acute myeloid leukaemia; hematopoietic stem cells; leukemic stem cells; lipid metabolism; sphingolipids
    DOI:  https://doi.org/10.1042/EBC20220028
  3. Biomedicines. 2022 Aug 15. pii: 1972. [Epub ahead of print]10(8):
    Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations.
    Fangliang Zhang, Liang Chen.
      Splicing factors are frequently mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations are presumed to contribute to oncogenic transformation, but the underlying mechanisms remain incompletely understood. While no specific treatment option is available for MDS/AML patients with spliceosome mutations, novel targeting strategies are actively explored, leading to clinical trials of small molecule inhibitors that target the spliceosome, DNA damage response pathway, and immune response pathway. Here, we review recent progress in mechanistic understanding of splicing factor mutations promoting disease progression and summarize potential therapeutic strategies, which, if successful, would provide clinical benefit to patients carrying splicing factor mutations.
    Keywords:  DNA damage response; acute myeloid leukemia; immune response pathway; myelodysplastic syndromes; spliceosome
    DOI:  https://doi.org/10.3390/biomedicines10081972
  4. Mol Cancer Res. 2022 Aug 22. pii: MCR-21-1032. [Epub ahead of print]
    Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
    Alessia Roma, Matthew Tcheng, Nawaz Ahmed, Sarah Walker, Preethi Jayanth, Mark D Minden, Kristin Hope, Praveen P Nekkar Rao, Jessica Luc, Andrew C Doxey, Julie A Reisz, Rachel Culp-Hill, Angelo D'Alessandro, Paul A Spagnuolo.
      Acute myeloid leukemia (AML) is a hematological malignancy metabolically dependent on oxidative phosphorylation and mitochondrial electron transport chain (ETC) activity. AML cells are distinct from their normal hematopoietic counterparts by this metabolic reprogramming, which presents targets for new selective therapies. Here, metabolic changes in AML cells after ETC impairment are investigated. Genetic knockdown of the ETC complex II (CII) chaperone protein SDHAF1 (succinate dehydrogenase assembly factor 1) suppressed CII activity and delayed AML cell growth in vitro and in vivo. As a result, a novel small molecule that directly binds to the ubiquinone binding site of CII and inhibits its activity was identified. Pharmacological inhibition of CII induced selective cell death in AML cells while sparing normal hematopoietic progenitors. Through stable isotope tracing, results show that genetic or pharmacological inhibition of CII truncates the tricarboxylic acid cycle (TCA) and leads to anaplerotic glutamine metabolism to reestablish the truncated cycle. The inhibition of CII showed divergent fates of AML cells since they lacked the metabolic plasticity to adequately utilize glutamine metabolism, resulting in preferential depletion of key metabolites in the TCA cycle and death; normal cells were unaffected. These findings provide insight into the metabolic mechanisms that underlie AML's selective inhibition of CII. Implications: This work highlights the effects of direct CII inhibition in mediating selective AML cell death and provides insights into glutamine anaplerosis as a metabolic adaptation that can be therapeutically targeted.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-1032
  5. Life (Basel). 2022 Jul 28. pii: 1135. [Epub ahead of print]12(8):
    Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm.
    Charles Gaulin, Katalin Kelemen, Cecilia Arana Yi.
      Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion. Inflammation, microbiome signatures, and external selective pressures also contribute to clonal evolution. Despite significant progress in recent years, the precise molecular mechanisms driving CH transformation to hematologic neoplasms are not well defined. Further understanding of these complex mechanisms may improve risk stratification and introduce therapeutic interventions in CH. Here we discuss the genetic drivers underpinning CH, mechanisms for clonal evolution, and transformation to hematologic neoplasm.
    Keywords:  aging; clonal hematopoiesis; hematologic neoplasms; hematopoietic stem cell
    DOI:  https://doi.org/10.3390/life12081135
  6. Leukemia. 2022 Aug 25.
    Current status and future perspectives in targeted therapy of NPM1-mutated AML.
    Roberta Ranieri, Giulia Pianigiani, Sofia Sciabolacci, Vincenzo Maria Perriello, Andrea Marra, Valeria Cardinali, Sara Pierangeli, Francesca Milano, Ilaria Gionfriddo, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini.
      Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30-35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.
    DOI:  https://doi.org/10.1038/s41375-022-01666-2
  7. Haematologica. 2022 Aug 25.
    Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia.
    Binay K Sahoo, Yuh-Charn Lin, Cheng-Fen Tu, Chien-Chin Lin, Wei-Ju Liao, Fu-An Li, Ling-Hui Li, Kurt Yun Mou, Steve R Roffler, Shu-Ping Wang, Chi-Tai Yeh, Chi-Yuan Yao, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien, Ruey-Bing Yang.
      A hallmark of mixed lineage leukemia gene-rearranged (MLL-r) acute myeloid leukemia (AML) that offers an opportunity for targeted therapy is addiction to protein-tyrosine kinase (TK) signaling. One such signaling is the receptor TK (RTK) Fms-like receptor tyrosine kinase 3 (FLT3) upregulated by cooperation of the transcription factors homeobox A9 (HOXA9) and Meis homeobox 1 (MEIS1). Signal peptide-CUB-EGF-like repeat-containing protein (SCUBE) family previously shown to act as a co-receptor for augmenting signaling activity of an RTK (e.g., vascular endothelial growth factor receptor). However, whether SCUBE1 is involved in the pathological activation of FLT3 during MLL-r leukemogenesis remains unknown. Here we first show that SCUBE1 is a direct target of HOXA9/MEIS1 that is highly expressed on the MLL-r cell surface and predicts poor prognosis in de novo AML. We further demonstrate by using a conditional knockout mouse model that Scube1 is required for both the initiation and maintenance of MLL-AF9-induced leukemogenesis in vivo. Further proteomic, molecular and biochemical analyses reveal that the membrane-tethered SCUBE1 binds to the FLT3 ligand and the extracellular ligand-binding domains of FLT3, thus facilitating activation of the signal axis FLT3-LYN (a nonreceptor TK) to initiate leukemic growth and survival signals. Importantly, targeting surface SCUBE1 by an anti-SCUBE1 monomethyl auristatin E antibody-drug conjugate led to significantly decreased cell viability specifically in MLL-r leukemia. Our study reports a novel function of SCUBE1 in leukemia and unravels the molecular mechanism of SCUBE1 in MLL-r AML. Thus, SCUBE1 is a potential therapeutic target for treating leukemia caused by MLL rearrangements.
    DOI:  https://doi.org/10.3324/haematol.2022.281151
  8. Clin Cancer Res. 2022 Aug 25. pii: CCR-22-1183. [Epub ahead of print]
    Outcomes in Patients With Poor-risk Cytogenetics With or Without TP53 Mutations Treated With Venetoclax and Azacitidine.
    Daniel A Pollyea, Keith W Pratz, Andrew H Wei, Vinod Pullarkat, Brian A Jonas, Christian Recher, Sunil Babu, Andre C Schuh, Monique Dail, Yan Sun, Jalaja Potluri, Brenda Chyla, Courtney D DiNardo.
       PURPOSE: Evaluate efficacy and safety of venetoclax+azacitidine in treatment-naïve patients with AML harboring poor-risk cytogenetics and TP53mut or TP53wt.
    PATIENTS AND METHODS: We analyzed data from a phase-3 study (NCT02993523) comparing venetoclax (400 mg orally days 1-28)+azacitidine (75 mg/m2 days 1-7) or placebo+azacitidine, and a phase-1b study (NCT02203773) of venetoclax+azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.
    RESULTS: 127 patients with poor-risk cytogenetics receiving venetoclax+azacitidine (TP53wt=50; TP53mut=54) were compared to 56 patients with poor-risk cytogenetics receiving azacitidine alone (TP53wt=22; TP53mut=18). For poor-risk cytogenetics+TP53wt, venetoclax+azacitidine vs. azacitidine alone resulted in composite remission rates (CRc) of 70% vs. 23%, median DoR of 18.4 vs. 8.5 months, and median OS of 23.4 vs. 11.3 months, respectively. Outcomes with venetoclax+azacitidine were comparable to similarly-treated patients with intermediate-risk cytogenetics+TP53wt. For poor-risk cytogenetics+TP53mut, venetoclax+azacitidine vs. azacitidine alone resulted in CRc of 41% vs. 17%, median DoR of 6.5 vs. 6.7 months, and median OS of 5.2 vs. 4.9 months, respectively. For poor-risk cytogenetics+TP53mut, predominant grade ≥3 adverse events (AEs) for venetoclax+azacitidine/azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt.
    CONCLUSIONS: In poor-risk cytogenetics+TP53mut patients, venetoclax+azacitidine improved remission rates but not DoR or OS compared to azacitidine alone. However,in poor-risk cytogenetics+TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable to similarly-treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1183
  9. Exp Hematol. 2022 Aug 19. pii: S0301-472X(22)00679-8. [Epub ahead of print]
    EGR1 haploinsufficiency confers a fitness advantage to hematopoietic stem cells following chemotherapy.
    Angela Stoddart, Anthony A Fernald, Elizabeth M Davis, Megan E McNerney, Michelle M Le Beau.
      Therapy-related myeloid neoplasms (t-MNs) share many clinical and molecular characteristics with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation, likely due to advanced age or chemotherapy-induced senescence. Here, we examined the impact of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs. In mice, under the exogenous stress of either serial transplant or successive doses of the alkylating agent ENU, Egr1-haploinsufficient hematopoietic stem cells (HSCs) exhibit a clonal advantage. Complete loss of EGR1 function is incompatible with transformation; mutations of EGR1 are rare and are not observed in the remaining allele in del(5q) patients and complete knockout of Egr1 in mice leads to HSC exhaustion. Using chromatin immunoprecipitation sequencing (ChIP-seq), we identified EGR1 binding sites in human CD34+ cord blood-derived stem and progenitor cells (HSPCs) and found that EGR1 binds genes critical for stem cell differentiation, inflammatory signaling, and the DNA damage response. Notably, in the chromosome 5 sequences frequently deleted in patients, there is a significant enrichment of innate and inflammatory genes, which may confer a fitness advantage in an inflammatory environment. Short hairpin RNA (shRNA) mediated silencing of EGR1 biases HSPCs towards a self-renewal transcriptional signature. In the absence of EGR1, HSPCs are characterized by upregulated MYC-driven proliferative signals, downregulated CDKN1A (p21), disrupted DNA damage response, and downregulated inflammation - adaptations anticipated to confer a relative fitness advantage for stem cells especially in an environment of chronic inflammation.
    DOI:  https://doi.org/10.1016/j.exphem.2022.08.003
  10. Blood Cancer J. 2022 Aug 22. 12(8): 122
    The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation.
    Ruth Meier, Gabriele Greve, Dennis Zimmer, Helena Bresser, Bettina Berberich, Ralitsa Langova, Julia Stomper, Anne Rubarth, Lars Feuerbach, Daniel B Lipka, Joschka Hey, Björn Grüning, Benedikt Brors, Justus Duyster, Christoph Plass, Heiko Becker, Michael Lübbert.
      The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a "viral mimicry" response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.
    DOI:  https://doi.org/10.1038/s41408-022-00715-4
  11. Biomedicines. 2022 Jul 30. pii: 1841. [Epub ahead of print]10(8):
    Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias.
    Xingjian Zhai, Xiaoyan Jiang.
      Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.
    Keywords:  acute myeloid leukemia; chronic myeloid leukemia; combination therapy; drug resistance; leukemic stem cells; metabolism; multi-omics; signal transduction; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines10081841
  12. Leukemia. 2022 Aug 23.
    Impact of emerging ACA on survival in chronic myeloid leukemia (CML).
    Rüdiger Hehlmann, Michael Lauseker, Astghik Voskanyan, Alice Fabarius, Claudia Haferlach, Andreas Hochhaus, Susanne Saußele.
      
    DOI:  https://doi.org/10.1038/s41375-022-01681-3
  13. Front Oncol. 2022 ;12 903691
    Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition.
    Jan Vorwerk, Kaiyan Sun, Daria Frank, Felix Neumann, Jana Hüve, Paulina Marie Budde, Longlong Liu, Xiaoqing Xie, Pradeep Kumar Patnana, Helal Mohammed Mohammed Ahmed, Bertram Opalka, Georg Lenz, Ashok Kumar Jayavelu, Cyrus Khandanpour.
      The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.
    Keywords:  Cdk inhibition; Cdks; Gfi1; acute myeloid leukemia; palbociclib; single nucleotide polymorphism
    DOI:  https://doi.org/10.3389/fonc.2022.903691
  14. Ann Hematol. 2022 Aug 23.
    Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.
    A Luna, L Pérez-Lamas, C Boque, P Giraldo, B Xicoy, C Ruiz Nuño, M Moreno Vega, A Alvarez-Larrán, A Salamanca, A García-Noblejas, F Vall-Llovera, L Villalon, N De Las Heras, E Ramila, M Pérez-Encinas, B Cuevas, R Perez-Lopez, F Sanchez-Guijo, A Jiménez-Velasco, S Lakhwani, L Felipe Casado, A Rosell, A Escola, M J Fernández, C Garcia-Hernandez, C Cervero, E Mora, M Sagüés, S Suarez-Varela, P Vélez, P Carrascosa Mastell, R F Bitaube, L Serrano, M Cortes, J A Vera Goñi, J L Steegmann, V Gomez Garcia de Soria, J M Alonso-Dominguez, M Colorado Araujo, A Paz Coll, J C Hernandez-Boluda, V García-Gutiérrez.
      Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.
    Keywords:  Asciminib; Inhibitors; Leukemia
    DOI:  https://doi.org/10.1007/s00277-022-04932-6
  15. Haematologica. 2022 Aug 25.
    An open-label, phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858, an unconjugated anti-CD33 monoclonal antibody, in combination with decitabine in patients with acute myeloid leukemia.
    Walter Fiedler, Pau Montesinos, Christoph Schliemann, Jan Middeke, Sumithira Vasu, Christian W Scholz, Jordi Esteve, Shoubhik Mondal, Björn Rüter, Ute Burkard, Annika Osswald, William Blum.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.281128
  16. Biomedicines. 2022 Aug 04. pii: 1881. [Epub ahead of print]10(8):
    NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition.
    Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield, Håkon Reikvam.
      The prognosis of acute myeloid leukemia (AML) is poor, especially for the elderly population. Targeted therapy with small molecules may be a potential strategy to overcome chemoresistance and improve survival in AML. We investigated the inhibition of the signaling molecule ras-related C3 botulinum toxin substrate 1 (Rac1) in leukemia cells derived from 79 consecutive AML patients, using five Rac1 inhibitors: ZINC69391, ITX3, EHOP-016, 1A-116, and NSC23766. In vitro cell proliferation and apoptosis assays and the assessment of cytokine profiles in culture media were conducted. All five inhibitors had an antiproliferative effect; IC50 ranged from 3-24 µM. They induced significant apoptosis and necrosis compared to the untreated controls (p < 0.0001) at concentrations around IC40 and IC80. A high versus an intermediate or low antiproliferative effect was more common in NPM1-mutated (p = 0.002) and CD34-negative (p = 0.008) samples, and when NPM1 and FLT3 (p = 0.027) were combined. Presence of NPM1 mutation was associated with reduced viability after treatment with EHOP-016 (p = 0.014), ITX3 (p = 0.047), and NSC23766 (p = 0.003). Several cytokines crucial for leukemogenesis were reduced after culture, with the strongest effects observed for 1A-116 and NSC23766. Our findings suggest potent effects of Rac1 inhibition in primary AML cells and, interestingly, samples harboring NPM1 mutation seem more vulnerable.
    Keywords:  AML; GTPase; NPM1; Rac1; cytokines; signaling molecule
    DOI:  https://doi.org/10.3390/biomedicines10081881
  17. Blood Rev. 2022 Aug 02. pii: S0268-960X(22)00070-4. [Epub ahead of print] 100996
    Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives.
    Ian M Bouligny, Keri R Maher, Steven Grant.
      Acute myeloid leukemia (AML) is a heterogeneous hematopoietic neoplasm which results in clonal proliferation of abnormally differentiated hematopoietic cells. In this review, mechanisms contributing to myeloid leukemogenesis are summarized, highlighting aberrations of epigenetics, transcription factors, signal transduction, cell cycling, and the bone marrow microenvironment. The mechanisms contributing to AML are detailed to spotlight recent findings that convey clinical impact. The applications of current and prospective therapeutic targets are accentuated in addition to reviews of treatment paradigms stratified for each characteristic molecular lesion - with a focus on exploring novel treatment approaches and combinations to improve outcomes in AML.
    Keywords:  Acute myeloid leukemia; Cell cycle; Epigenetics; Leukemogenesis; Novel strategies; Oncoprotein; Signal transduction; Targeted therapy; Transcription factor
    DOI:  https://doi.org/10.1016/j.blre.2022.100996
  18. iScience. 2022 Aug 19. 25(8): 104787
    A tubulin binding molecule drives differentiation of acute myeloid leukemia cells.
    Thomas R Jackson, Aini Vuorinen, Laia Josa-Culleré, Katrina S Madden, Daniel Conole, Thomas J Cogswell, Isabel V L Wilkinson, Laura M Kettyle, Douzi Zhang, Alison O'Mahony, Deanne Gracias, Lorna McCall, Robert Westwood, Georg C Terstappen, Stephen G Davies, Edward W Tate, Graham M Wynne, Paresh Vyas, Angela J Russell, Thomas A Milne.
      Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.
    Keywords:  Biological sciences; Cancer; Chemistry; Molecular biology; Molecular medicine
    DOI:  https://doi.org/10.1016/j.isci.2022.104787
  19. Blood. 2022 Aug 25. 140(8): 800-801
    Mutant SF3B1 splices a more leukemogenic EVI1.
    Esther A Obeng.
      
    DOI:  https://doi.org/10.1182/blood.2022017380
  20. Blood Rev. 2022 Aug 15. pii: S0268-960X(22)00075-3. [Epub ahead of print] 101001
    CHIPing away the progression potential of CHIP: A new reality in the making.
    Zhuoer Xie, Amer M Zeidan.
      Over the past few years, we have gained a deeper understanding of clonal hematopoiesis of indeterminate potential (CHIP), especially with regard to the epidemiology, clinical sequelae, and mechanical aspects. However, interventional strategies to prevent or delay the potential negative consequences of CHIP remain underdeveloped. In this review, we highlight the latest updates on clonal hematopoiesis research, including molecular mechanisms and clinical implications, with a particular focus on the evolving strategies for the interventions that are being evaluated in ongoing observational and interventional trials. There remains an urgent need to formulate standardized and evidence-based recommendations and guidelines for evaluating and managing individuals with clonal hematopoiesis. In addition, patient-centric endpoints must be defined for clinical trials, which will enable us to continue the robust development of effective preventive strategies and improve clinical outcomes.
    Keywords:  Aging; CCUS; CHIP; Inflammation; Intervention; Prevention
    DOI:  https://doi.org/10.1016/j.blre.2022.101001
  21. Sci Adv. 2022 Aug 26. 8(34): eabn5522
    DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells.
    Yale S Michaels, John M Edgar, Matthew C Major, Elizabeth L Castle, Carla Zimmerman, Ting Yin, Andrew Hagner, Charles Lau, Han Hsuan Hsu, M Iliana Ibañez-Rios, Lauren J Durland, David J H F Knapp, Peter W Zandstra.
      T cells show tremendous efficacy as cellular therapeutics. However, obtaining primary T cells from human donors is expensive and variable. Pluripotent stem cells (PSCs) have the potential to provide a renewable source of T cells, but differentiating PSCs into hematopoietic progenitors with T cell potential remains an important challenge. Here, we report an efficient serum- and feeder-free system for differentiating human PSCs into hematopoietic progenitors and T cells. This fully defined approach allowed us to study the impact of individual proteins on blood emergence and differentiation. Providing DLL4 and VCAM1 during the endothelial-to-hematopoietic transition enhanced downstream progenitor T cell output by ~80-fold. These two proteins synergized to activate notch signaling in nascent hematopoietic stem and progenitor cells, and VCAM1 additionally promoted an inflammatory transcriptional program. We also established optimized medium formulations that enabled efficient and chemically defined maturation of functional CD8αβ+, CD4-, CD3+, TCRαβ+ T cells with a diverse TCR repertoire.
    DOI:  https://doi.org/10.1126/sciadv.abn5522
  22. Br J Haematol. 2022 Aug 24.
    Management of older patients with frailty and acute myeloid leukaemia: A British Society for Haematology good practice paper.
    Mike Dennis, Mhairi Copland, Harpreet Kaur, Jonathan Kell, Emmanouil Nikolousis, Priyanka Mehta, Renuka Palanicawandar, Victoria Potter, Kavita Raj, Ian Thomas, Andrew Wilson.
      
    DOI:  https://doi.org/10.1111/bjh.18369
  23. J Clin Med. 2022 Aug 21. pii: 4908. [Epub ahead of print]11(16):
    Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS.
    Maria Velegraki, Andrew Stiff, Helen A Papadaki, Zihai Li.
      Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by the clonal expansion of hematopoietic stem cells, bone marrow failure manifested by cytopenias, and increased risk for evolving to acute myeloid leukemia. Despite the fact that the acquisition of somatic mutations is considered key for the initiation of the disease, the bone marrow microenvironment also plays significant roles in MDS by providing the right niche and even shaping the malignant clone. Aberrant immune responses are frequent in MDS and are implicated in many aspects of MDS pathogenesis. Recently, myeloid-derived suppressor cells (MDSCs) have gained attention for their possible implication in the immune dysregulation associated with MDS. Here, we summarize the key findings regarding the expansion of MDSCs in MDS, their role in MDS pathogenesis and immune dysregulation, as well their potential as a new therapeutic target for MDS.
    Keywords:  bone marrow failure; immune dysregulation; myelodysplastic syndromes; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.3390/jcm11164908
  24. Blood Adv. 2022 Aug 24. pii: bloodadvances.2022008061. [Epub ahead of print]
    Longitudinal metabolic study of red blood cells from patients undergoing gender-affirming testosterone therapy.
    Micaela Kalani Roy, Rebecca Burgoyne Wilkerson, Keisha Alexander, Natalie J Nokoff, Melanie Cree-Green, Angelo D'Alessandro.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022008061
  25. Haematologica. 2022 Aug 25.
    Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications.
    Christer Nilsson, Fredrika Linde, Erik Hulegårdh, Hege Garelius, Vladimir Lazarevic, Petar Antunovic, Jörg Cammenga, Stefan Deneberg, Anna Eriksson, Martin Jädersten, Cecilia Kämpe Björkvall, Lars Möllgård, Lovisa Wennström, Emma Ölander, Martin Höglund, Gunnar Juliusson, Sören Lehmann.
      Studies of therapy-related AML (t-AML) are usually performed in selected cohorts and reliable incidence rates are lacking. In this study, we characterized, defined the incidence over time and studied prognostic implications in all t-AML patients diagnosed in Sweden between 1997 and 2015. Data were retrieved from nationwide population-based registries. In total, 6779 AML patients were included in the study, of which 686 (10%) had t-AML. The median age for t-AML was 71 years and 392 (57%) patients were females. During the study period, the incidence of t-AML almost doubled with a yearly increase in t-AML of 4.5% (CI 2.8% - 6.2%), which contributed significantly to the general increase in AML incidence over the study period. t-AML solidly constituted over 10% of all AML cases during the later study period. Primary diagnoses with the largest increase in incidence and decrease in mortality rate during the study period (i.e. breast and prostate cancer) contributed significantly to the increased incidence of t-AML. In multivariable analysis, t-AML was associated with poorer outcome in cytogenetically intermediate and adverse risk but t-AML had no significant impact on outcome in favorable risk AML, including core binding leukemias, APL and AML with mutated NPM1 without FLT3-ITD. We conclude that t-AML displays a strong increase in incidence over time and that t-AML constitutes a successively larger proportion of the AML patients. Furthermore, we conclude that t-AML confer a poor prognosis in cytogenetically intermediate and adverse risk, but not in favorable risk AML.
    DOI:  https://doi.org/10.3324/haematol.2022.281233
  26. Haematologica. 2022 Aug 25.
    ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.
    Zhongxun Shi, Jinqin Liu, Yingying Zhao, Lin Yang, Yanan Cai, Peihong Zhang, Zefeng Xu, Tiejun Qin, Shiqiang Qu, Lijuan Pan, Junying Wu, Xin Yan, Zexing Li, Wenjun Zhang, Yiru Yan, Huijun Huang, Gang Huang, Bing Li, Xudong Wu, Zhijian Xiao.
      Apart from the central role of activated JAK/STAT signaling pathway, ASXL1 mutations are the most recurrent additional mutations in myeloproliferative neoplasms (MPNs) and occurred much more common in myelofibrosis (MF) than essential thrombocythemia (ET) and polycythemia vera (PV) patients. However, the mechanism of the association with ASXL1 mutations and bone marrow (BM) fibrosis remains unknown. Here, integrating our own data of MPN patients and hematopoietic-specific Asxl1 deletion/Jak2V617F mouse model, we show that ASXL1 mutations are associated with advanced MPN phenotypes and onset of myelofibrosis. ASXL1 mutations induce skewed monocyte/macrophage and neoplastic monocyte-derived fibrocyte differentiation, consequently enhance inflammation and BM fibrosis. Consistently, the loss of ASXL1 and JAK2V617F mutation in hematopoietic stem and progenitor cells (HSPCs) leads to enhancer activation of polycomb group (PcG) target genes, such as EGR1. The upregulation of EGR1, in turn accounts for increased HSPCs commitment to monocyte/macrophage lineage. Moreover, EGR1 induces the activation of TNFA and thereby further drives the differentiation of monocytes to fibrocytes. Accordingly, combined TNFR antagonist with ruxolitinib significantly reduces fibrocytes production in vitro. Altogether, these findings demonstrate that ASXL1 mutations accelerate fibrocyte production and inflammation in MPNs via EGR1-TNFA axis, providing cellular and molecular basis for BM fibrosis and proof-of-concept for anti-fibrosis treatment.
    DOI:  https://doi.org/10.3324/haematol.2021.280320
  27. J Clin Oncol. 2022 Aug 23. JCO2102476
    Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study.
    Uwe Platzbecker, Katharina S Götze, Philipp Kiewe, Ulrich Germing, Karin Mayer, Markus Radsak, Thomas Wolff, Joerg Chromik, Katja Sockel, Uta Oelschlägel, Detlef Haase, Thomas Illmer, Haifa Kathrin Al-Ali, Gerda Silling, Joseph G Reynolds, Xiaosha Zhang, Kenneth M Attie, Jeevan K Shetty, Aristoteles Giagounidis.
      Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Luspatercept has high clinical activity in patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and ring sideroblasts (RS) relapsed or refractory to erythropoietin. We report long-term luspatercept safety and efficacy in 108 patients with LR-MDS in the PACE-MDS study, including 44 non-RS and 34 non-transfusion-dependent or previously untreated patients. The primary end point was safety. Secondary end points included rates of hematologic improvement (HI) erythroid (HI-E), HI neutrophil, and HI platelet. Exploratory end points included erythropoiesis biomarker quantitation and mutation data. Median duration of luspatercept exposure was 315 days (range, 21-1,934 days). No new safety signals emerged. HI-E was observed in 53.7% of patients, including 36.4% of non-RS and 70.6% of non-transfusion-dependent patients. HI neutrophil and HI platelet were observed in 33.3% and 9.5% of patients, respectively. An almost three-fold increase in bone marrow late to early progenitor cell ratio accompanied HI-E response, irrespective of RS status. Lower baseline erythropoietin levels in non-RS patients (69.6 v 623.3 IU/L; P = .0077) and higher late to early erythroid progenitor cell ratio (10.44 v 4.48; P = .0106) in RS patients were associated with HI-E. This study highlights luspatercept's effects across LR-MDS subtypes, including untreated MDS-RS, serving as a platform for future trials.
    DOI:  https://doi.org/10.1200/JCO.21.02476
  28. Br J Cancer. 2022 Aug 23.
    Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.
    Seungyeon Jung, Emma Armstrong, Alexander Z Wei, Fei Ye, Aaron Lee, Matteo S Carlino, Ryan J Sullivan, Richard D Carvajal, Alexander N Shoushtari, Douglas B Johnson.
       BACKGROUND: Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined.
    METHODS: We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients. Baseline patient and disease characteristics, and clinical outcomes were assessed.
    RESULTS: In the pooled analysis (N = 130), alterations in exons 11/13 had the highest response rates (38% and 33%); L576P (N = 23) and K642E (N = 12) mutations had ORR of 52% and 42%, respectively. ORR was 38% (mucosal), 25% (acral), and 8% (unknown-primary). PFS appeared longer in exon 11/13 vs. exon 17 alterations (median 4.3 and 4.5 vs. 1.1 months; p = 0.19), with similar superiority in OS (median 19.7 and 15.4 vs. 12.1 months; p = 0.20). By histology, median PFS was 4.5 months (mucosal), 2.7 (acral), and 5.0 (unknown-primary) [p = 0.36]. Median OS was 18.0 months (mucosal), 21.8 (acral), 11.5 (unknown-primary) [p = 0.26]. In multivariate analyses, mucosal melanoma was associated with higher PFS and exon 17 mutations were associated with reduced PFS.
    CONCLUSION: This multicenter study highlights KIT-alterations sensitive to imatinib and augments evidence for imatinib in subsets of KIT-altered melanoma.
    DOI:  https://doi.org/10.1038/s41416-022-01942-z
  29. Cell Biol Int. 2022 Aug 23.
    Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34+  hematopoietic stem and progenitor cells.
    Jyotika Srivastava, Shobhita Katiyar, Chandra P Chaturvedi, Soniya Nityanand.
      Mesenchymal stromal cells (MSC) regulate hematopoiesis in the bone marrow (BM) niche and extracellular vesicles (EVs) released by BM-MSC are important mediators of the cross-talk between BM-MSC and hematopoietic stem and progenitor cells (HSPC). We have previously demonstrated that BM-MSC of severe aplastic anemia (SAA) patients have an altered expression of hematopoiesis regulatory molecules. In the present study, we observed that CD34+ HSPC when cocultured with BM-MSC EVs from aplastic anemia patients exhibited a significant reduction in colony-forming units (p = .001), cell proliferation (p = .002), and increased apoptosis (p > .001) when compared to coculture with BM-MSC EVs from controls. Collectively, our results highlight that EVs derived from the BM-MSC of SAA patients impair the hematopoiesis supporting function of HSPC.
    Keywords:  aplastic anemia; apoptosis; bone marrow mesenchymal stromal cells; colony forming units; extracellular vesicles; hematopoisis
    DOI:  https://doi.org/10.1002/cbin.11885
  30. Blood Adv. 2022 Aug 24. pii: bloodadvances.2022008172. [Epub ahead of print]
    Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.
    Caner Saygin, Gregory W Roloff, Christopher N Hahn, Rakchha Chhetri, Saar I Gill, Hany Elmariah, Chetasi Talati, Emma Nunley, Guimin Gao, Aelin Kim, Michael R Bishop, Satyajit Kosuri, Soma Das, Deepak Singhal, Parvathy Venugopal, Claire Christine Homan, Anna L Brown, Hamish S Scott, Devendra K Hiwase, Lucy A Godley.
      There is increasing recognition that pathogenic germline variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germline predisposition variants have different post-transplant outcomes compared to those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germline variants (DGVs) and 34% underwent HSCT. DGVs in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germline DDX41 variants had a higher incidence of severe (stage 3-4) acute graft versus host disease (GVHD) (38%) compared to recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germline variants (9%) (p= 0.002). Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008172
  31. Nat Cancer. 2022 Aug;3(8): 911-926
    Cancer vaccines: the next immunotherapy frontier.
    Matthew J Lin, Judit Svensson-Arvelund, Gabrielle S Lubitz, Aurélien Marabelle, Ignacio Melero, Brian D Brown, Joshua D Brody.
      After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
    DOI:  https://doi.org/10.1038/s43018-022-00418-6
  32. Cancers (Basel). 2022 Aug 19. pii: 4006. [Epub ahead of print]14(16):
    FLT3-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia.
    Diego Carbonell, María Chicano, Alfonso J Cardero, Ignacio Gómez-Centurión, Rebeca Bailén, Gillen Oarbeascoa, Diana Martínez-Señarís, Carolina Franco, Paula Muñiz, Javier Anguita, Mi Kwon, José Luis Díez-Martín, Ismael Buño, Carolina Martínez-Laperche.
      FLT3-internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare FLT3-ITD mutation analysis in DNA and cDNA samples at diagnosis and to demonstrate the usefulness of its expression measurement as an MRD marker after allogeneic stem cell transplantation (allo-HSCT) or FLT3 inhibitor (FLT3i) administration. A total of 46 DNA and cDNA diagnosis samples, 102 DNA and cDNA post-allo-HSCT samples from 34 patients and 37 cDNA samples from 7 patients with refractory/relapse AML treated with FLT3i were assessed for the FLT3-ITD mutation through fragment analysis. In terms of sensitivity, the analysis of cDNA was superior to that of DNA, quantifying higher allelic ratio values in most cases at diagnosis, and thus optimizing the detection of minor clones and prognostic classification. Regarding the last sample before post-HSCT relapse, cDNA analysis anticipated relapse in most cases, unlike DNA analyses. With regard to the post-FLT3i follow-up, FLT3-ITD expression was reduced after the first FLT3i cycle when the treatment was effective, whereas it was not reduced in refractory patients. FLT3-ITD expression could be a useful additional biomarker at diagnosis and for the assessment of MRD after allo-HSCT and FLT3i in AML.
    Keywords:  FLT3-ITD gene expression; acute myeloid leukemia; allogeneic stem cell transplantation; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.3390/cancers14164006
  33. Exp Hematol. 2022 Aug 17. pii: S0301-472X(22)00677-4. [Epub ahead of print]
    Ubiquitin E3 ligase FBXO21 regulates cytokine mediated signaling pathways, but is dispensable for steady-state hematopoiesis.
    Karli J Wittorf, Kasidy K Weber, Samantha A Swenson, Shannon M Buckley.
      Hematopoietic cell fate decisions such as self-renewal and differentiation are highly regulated through multiple molecular pathways. One pathway, the ubiquitin proteasome system (UPS), controls protein levels by tagging them with polyubiquitin chains and promoting their degradation through the proteasome. Ubiquitin E3 ligases serve as the substrate-recognition component of the UPS. Through investigating the FBOX family of E3 ligases, we discovered that Fbxo21 was highly expressed in the hematopoietic stem and progenitor cell (HSPC) population, and showed low to no expression in mature myeloid populations. To determine the role of FBXO21 on HSPC maintenance, self-renewal, and differentiation, we generated shRNAs against FBXO21 and a hematopoietic specific Fbxo21 conditional knockout (cKO) mouse model. We found that silencing FBXO21 in HSPCs led to a loss in colony formation and an increase in cell differentiation in vitro. Additionally, stressing the HSPC populations in our Fbxo21 cKO mouse with 5-FU injections resulted in a decrease in survival, despite these populations showing minimal alterations during steady-state hematopoiesis. Although FBXO21 has previously been proposed to regulate cytokine signaling via ASK and p38, our results show that depletion of FBXO21 led to altered ERK signaling in vitro. Together, these findings suggest ubiquitin E3 ligase FBXO21 regulates HSPCs through cytokine mediated pathways.
    DOI:  https://doi.org/10.1016/j.exphem.2022.08.002
  34. iScience. 2022 Aug 19. 25(8): 104760
    Identifying mutant-specific multi-drug combinations using comparative network reconstruction.
    Evert Bosdriesz, João M Fernandes Neto, Anja Sieber, René Bernards, Nils Blüthgen, Lodewyk F A Wessels.
      Targeted inhibition of aberrant signaling is an important treatment strategy in cancer, but responses are often short-lived. Multi-drug combinations have the potential to mitigate this, but to avoid toxicity such combinations must be selective and given at low dosages. Here, we present a pipeline to identify promising multi-drug combinations. We perturbed an isogenic PI3K mutant and wild-type cell line pair with a limited set of drugs and recorded their signaling state and cell viability. We then reconstructed their signaling networks and mapped the signaling response to changes in cell viability. The resulting models, which allowed us to predict the effect of unseen combinations, indicated that no combination selectively reduces the viability of the PI3K mutant cells. However, we were able to validate 25 of the 30 combinations that we predicted to be anti-selective. Our pipeline enables efficient prioritization of multi-drug combinations from the enormous search space of possible combinations.
    Keywords:  Bioinformatics; In silico biology; Pharmacoinformatics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104760
  35. Nat Metab. 2022 Aug;4(8): 1041-1054
    N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
    Hao Peng, Binbin Chen, Wei Wei, Siyao Guo, Hui Han, Chunlong Yang, Jieyi Ma, Lu Wang, Sui Peng, Ming Kuang, Shuibin Lin.
      Aberrant RNA modifications lead to dysregulated gene expression and cancer progression. Ribosomal RNA (rRNA) accounts for more than 80% of a cell's total RNA, but the functions and molecular mechanisms underlying rRNA modifications in cancers are poorly understood. Here, we show that the 18S rRNA N6-methyladenosine (m6A) methyltransferase complex METTL5-TRMT112 is upregulated in various cancer types and correlated with poor prognosis. In addition, we demonstrate the critical functions of METTL5 in promoting hepatocellular carcinoma (HCC) tumorigenesis in vitro and in mouse models. Mechanistically, depletion of METTL5-mediated 18S rRNA m6A modification results in impaired 80S ribosome assembly and decreased translation of mRNAs involved in fatty acid metabolism. We further reveal that ACSL4 mediates the function of METTL5 on fatty acid metabolism and HCC progression, and targeting ACSL4 and METTL5 synergistically inhibits HCC tumorigenesis in vivo. Our study uncovers mechanistic insights underlying mRNA translation control and HCC tumorigenesis through lipid metabolism remodeling and provides a molecular basis for the development of therapeutic strategies for HCC treatment.
    DOI:  https://doi.org/10.1038/s42255-022-00622-9
  36. Nat Commun. 2022 Aug 26. 13(1): 5033
    DAXX-ATRX regulation of p53 chromatin binding and DNA damage response.
    Nitish Gulve, Chenhe Su, Zhong Deng, Samantha S Soldan, Olga Vladimirova, Jayamanna Wickramasinghe, Hongwu Zheng, Andrew V Kossenkov, Paul M Lieberman.
      DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT). Here, we show that DAXX and ATRX knock-out (KO) U87-T cells that have acquired ALT-like features have defects in p53 chromatin binding and DNA damage response. RNA-seq analysis revealed that p53 pathway is among the most perturbed. ChIP-seq and ATAC-seq revealed a genome-wide reduction in p53 DNA-binding and corresponding loss of chromatin accessibility at many p53 response elements across the genome. Both DAXX and ATRX null cells showed a depletion of histone H3.3 and accumulation of γH2AX at many p53 sites, including subtelomeres. These findings indicate that loss of DAXX or ATRX can compromise p53 chromatin binding and p53 DNA damage response in ALT-like cells, providing a link between histone composition, chromatin accessibility and tumor suppressor function of p53.
    DOI:  https://doi.org/10.1038/s41467-022-32680-8
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