bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒06‒11
24 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. An Old Dog Has a New Trick: Somatic Exonic Deletions in RUNX1 Are Frequent in AML.
  2. Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold.
  3. Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study.
  4. Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies.
  5. Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
  6. Framework of clonal mutations concurrent with WT1 mutations in adults with acute myeloid leukemia (Alliance).
  7. Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.
  8. Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes.
  9. Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance.
  10. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.
  11. How I read an article that uses machine learning methods.
  12. Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification.
  13. Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
  14. Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin.
  15. Secondary bile acids function through the vitamin D receptor in myeloid progenitors to promote myelopoiesis.
  16. Double, double, TP53, and trouble in myelofibrosis.
  17. Bridging to transplant and post-transplant maintenance therapy with FLT3 inhibitors in patients with relapsed or refractory FLT3 mutated acute myeloid leukemia.
  18. Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase-II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS).
  19. Loss of the mitochondrial protein Abcb10 results in altered arginine metabolism in MEL and K562 cells and nutrient stress signaling through ATF4.
  20. Lipid Nanoparticles Allow Efficient and Harmless Ex Vivo Gene Editing of Human Hematopoietic Cells.
  21. CNL and aCML are prognostically distinct: a large national cancer database analysis.
  22. Heritable transcriptional defects from aberrations of nuclear architecture.
  23. Epigenetic dysregulation from chromosomal transit in micronuclei.
  24. Immunotherapy in leukaemia.
  1. Clin Cancer Res. 2023 Jun 08. OF1-OF3
    An Old Dog Has a New Trick: Somatic Exonic Deletions in RUNX1 Are Frequent in AML.
    Joyeeta Chakraborty, Kristy R Stengel.
      Somatic loss-of-function RUNX1 mutations in acute myeloid leukemia (AML) include missense, nonsense, and frameshift mutations, whereas germline RUNX1 variants in RUNX1-FPDMM also include large exonic deletions. Alternative variant detection approaches revealed that large exonic deletions in RUNX1 are also common in sporadic AML, which has implications for patient stratification and therapeutic decision-making. See related article by Eriksson et al., p. 000.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1065
  2. Cancer Res. 2023 Jun 05. pii: CAN-23-1006. [Epub ahead of print]
    Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold.
    Emmanuel Griessinger, Diego Pereira-Martins, Marielle Nebout, Claudie Bosc, Estelle Saland, Emeline Boet, Ambrine Sahal, Johanna Chiche, Delphine Debayle, Lucile Fleuriot, Maurien Pruis, Veronique Mansat-De Mas, Francois Vergez, Christian Récher, Gerwin Huls, Jean-Emmanuel Sarry, Jan Jacob Schuringa, Jean-François Peyron.
      Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyzes showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1006
  3. Blood Adv. 2023 Jun 05. pii: bloodadvances.2023010179. [Epub ahead of print]
    Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study.
    Pierre Fenaux, Marco Gobbi, Patricia Kropf, Jean-Pierre J Issa, Gail J Roboz, Jiri Mayer, Jürgen Krauter, Tadeusz Robak, Hagop M Kantarjian, Jan Novak, Wieslaw Wiktor Jedrzejczak, Xavier Thomas, Mario Ojeda-Uribe, Yasushi Miyazaki, Yoo Hong Min, Su-Peng Yeh, Joseph M Brandwein, Liana Todorova Gercheva-Kyuchukova, Judit Demeter, Elizabeth A Griffiths, Karen W L Yee, Konstanze Döhner, Yong Hao, Harold Neal Keer, Mohammad Azab, Hartmut Döhner.
      This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia (AML) unfit to receive intensive induction chemotherapy. Half the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). Coprimary endpoints were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = 0.48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio 0.97; 95% confidence interval 0.83, 1.14; stratified log-rank P = 0.73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine, and 36% and 14% for TC. A large proportion of patients (42%) received <4 cycles of treatment in both arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio 0.78; 95% confidence interval 0.64, 0.96; log-rank P = 0.02]). There was no significant difference in the proportions of patients with grade ≥3 adverse events between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, there was no significant difference in efficacy between guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010179
  4. Clin Lymphoma Myeloma Leuk. 2023 May 15. pii: S2152-2650(23)00142-8. [Epub ahead of print]
    Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies.
    Manish R Patel, William Donnellan, Michael Byrne, Adam S Asch, Amer M Zeidan, Maria R Baer, Amir T Fathi, Andrew T Kuykendall, Fred Zheng, Chris Walker, Lulu Cheng, Cindy Marando, Michael R Savona.
      BACKGROUND: The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are implicated in tumorigenesis; the pan-PIM kinase inhibitor, INCB053914, demonstrated antitumor activity in hematologic malignancy preclinical models.PATIENTS AND METHODS: This phase 1/2 study evaluated oral INCB053914 alone or combined with standard-of-care agents for advanced hematologic malignancies (NCT02587598). In Parts 1/2 (monotherapy), patients (≥18 years) had acute leukemia, high-risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm, myelofibrosis (MF), multiple myeloma, or lymphoproliferative neoplasms. In Parts 3/4 (combination therapy), patients had relapsed/refractory or newly diagnosed (≥65 years, unfit for intensive chemotherapy) acute myeloid leukemia (AML) or MF with suboptimal ruxolitinib response.
    RESULTS: Parts 1/2 (n = 58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n = 4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n = 39): for INCB053914 + cytarabine (AML; n = 6), 2 patients experienced DLTs (grade 3 maculopapular rash, n = 1; grade 3 ALT-elevated and grade 4 hypophosphatemia, n = 1); for INCB053914 + azacitidine (AML; n = 16), 1 patient experienced a DLT (grade 3 maculopapular rash). Two complete responses were observed (1 with incomplete count recovery). For INCB053914 + ruxolitinib (MF; n = 17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24.
    CONCLUSION: INCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies.
    Keywords:  Acute myeloid leukemia; Myelofibrosis; Pharmacodynamics; Pharmacokinetics; Safety
    DOI:  https://doi.org/10.1016/j.clml.2023.05.002
  5. Cancer Immunol Res. 2023 Jun 07. OF1-OF18
    Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
    Poonam N Desai, Bofei Wang, Andre Fonseca, Pamella Borges, Fatima Zahra Jelloul, Patrick K Reville, Eric Lee, Christopher Ly, Akshay Basi, Jessica Root, Natalia Baran, Sean M Post, Qing Deng, Hanxiao Sun, Arif O Harmanci, Jared K Burks, Javier A Gomez, Courtney D DiNardo, Naval G Daver, Gheath Alatrash, Marina Konopleva, Michael R Green, Dinler A Antunes, Andrew Futreal, Dapeng Hao, Hussein A Abbas.
      Comprehensive investigation of CD8+ T cells in acute myeloid leukemia (AML) is essential for developing immunotherapeutic strategies beyond immune checkpoint blockade. Herein, we performed single-cell RNA profiling of CD8+ T cells from 3 healthy bone marrow donors and 23 newly diagnosed (NewlyDx) and 8 relapsed/refractory (RelRef) patients with AML. Cells coexpressing canonical exhaustion markers formed a cluster constituting <1% of all CD8+ T cells. We identified two effector CD8+ T-cell subsets characterized by distinct cytokine and metabolic profiles that were differentially enriched in NewlyDx and RelRef patients. We refined a 25-gene CD8-derived signature correlating with therapy resistance, including genes associated with activation, chemoresistance, and terminal differentiation. Pseudotemporal trajectory analysis supported enrichment of a terminally differentiated state in CD8+ T cells with high CD8-derived signature expression at relapse or refractory disease. Higher expression of the 25-gene CD8 AML signature correlated with poorer outcomes in previously untreated patients with AML, suggesting that the bona fide state of CD8+ T cells and their degree of differentiation are clinically relevant. Immune clonotype tracking revealed more phenotypic transitions in CD8 clonotypes in NewlyDx than in RelRef patients. Furthermore, CD8+ T cells from RelRef patients had a higher degree of clonal hyperexpansion associated with terminal differentiation and higher CD8-derived signature expression. Clonotype-derived antigen prediction revealed that most previously unreported clonotypes were patient-specific, suggesting significant heterogeneity in AML immunogenicity. Thus, immunologic reconstitution in AML is likely to be most successful at earlier disease stages when CD8+ T cells are less differentiated and have greater capacity for clonotype transitions.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0961
  6. Blood Adv. 2023 Jun 08. pii: bloodadvances.2023010482. [Epub ahead of print]
    Framework of clonal mutations concurrent with WT1 mutations in adults with acute myeloid leukemia (Alliance).
    Bhavana Bhatnagar, Jessica Kohlschmidt, Shelley Orwick, Daelynn R Buelow, Sydney Fobare, Christopher C Oakes, Jonathan E Kolitz, Geoffrey L Uy, Wendy Stock, Bayard L Powell, Deedra Nicolet, Erin Hertlein, Krzysztof Mrózek, James S Blachly, Ann-Kathrin Eisfeld, Sharyn D Baker, John C Byrd.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023010482
  7. medRxiv. 2023 May 17. pii: 2023.05.16.23290051. [Epub ahead of print]
    Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.
    Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Bryan Kestenbaum, Samuel A Silver, Jian-Chun Chen, Elvis Akwo, Pavan K Bhatraju, Ming-Zhi Zhang, Shirong Cao, Ming Jiang, Yinqiu Wang, Aolei Niu, Edward Siew, Holly J Kramer, Anna Kottgen, Nora Franceschini, Bruce M Psaty, Russell P Tracy, Alvaro Alonso, Dan E Arking, Josef Coresh, Christie M Ballantyne, Eric Boerwinkle, Morgan Grams, Matthew B Lanktree, Michael J Rauh, Raymond C Harris, Alexander G Bick.
      Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2 -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2 -CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2 -CHIP mice and Tet2 -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.
    DOI:  https://doi.org/10.1101/2023.05.16.23290051
  8. Blood Adv. 2023 Jun 05. pii: bloodadvances.2023010416. [Epub ahead of print]
    Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes.
    Sergiu Pasca, Matthew Z Guo, Shiyu Wang, Kristin Stokvis, Audra Shedeck, Aparna Pallavajjala, Cynthia Shams, Roshni Pallavajjala, Amy DeZern, Ravi Varadhan, Christopher D Gocke, Richard J Jones, Lukasz P Gondek.
      The measurable residual disease (MRD) assessment provides an attractive predictor of alloHCT outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohort including 82 patients participating in clinical trials (BMT CTN-0201 and 0402) were utilized. Ultra-deep error-corrected targeted sequencing was performed on plasma and bone marrow-derived DNA. We demonstrated that 94.6% (range 93.9-95.3%) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8, p<0.0001), however, cfDNA appeared to be more sensitive in detecting clones with variant allele frequency (VAF) <0.26%. CfDNA-MRD clearance by day 90 post-alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months, p <0.0001) and overall survival (OS, median survival not reached vs 7.3 months, p < 0.0001) when compared to patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs. 84.8%, p <0.0001) and RFS (16.7% vs. 80.7%, p <0.0001). CfDNA appears to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010416
  9. Elife. 2023 Jun 05. pii: e69322. [Epub ahead of print]12
    Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance.
    Virginia Folgado-Marco, Kristina Ames, Jacky Chuen, Kira Gritsman, Nicholas E Baker.
      Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps12. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12+/- genotype had growth and morphological defects, pancytopenia and impaired erythropoiesis. A striking reduction in hematopoietic stem cells (HSCs) and progenitors in the bone marrow (BM) was associated with decreased ability to repopulate the blood system after competitive and non-competitive BM transplantation. Rps12+/- mutants lost HSC quiescence, experienced ERK and MTOR activation and increased global translation in HSC and progenitors. Post-natal heterozygous deletion of Rps12 in hematopoietic cells using Tal1-Cre-ERT also resulted in pancytopenia with decreased HSC numbers. However, post-natal Cre-ERT induction led to reduced translation in HSCs and progenitors, suggesting that this is the most direct consequence of Rps12 haploinsufficiency in hematopoietic cells. Thus, RpS12 has a strong requirement in HSC function, in addition to erythropoiesis.
    Keywords:  developmental biology; mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.69322
  10. bioRxiv. 2023 May 27. pii: 2023.05.27.542323. [Epub ahead of print]
    Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.
    Jing Zeng, My Anh Nguyen, Pengpeng Liu, Lucas Ferreira da Silva, Linda Y Lin, David G Justus, Karl Petri, Kendell Clement, Shaina N Porter, Archana Verma, Nola R Neri, Tolulope Rosanwo, Marioara-Felicia Ciuculescu, Daniela Abriss, Esther Mintzer, Stacy A Maitland, Selami Demirci, John F Tisdale, David A Williams, Lihua Julie Zhu, Shondra M Pruett-Miller, Luca Pinello, J Keith Joung, Vikram Pattanayak, John P Manis, Myriam Armant, Danilo Pellin, Christian Brendel, Scot A Wolfe, Daniel E Bauer.
      Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here we compared combined CRISPR-Cas9 endonuclease editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. We found that combined targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two sgRNAs resulted in superior HbF induction, including in engrafting erythroid cells from sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers. We corroborated prior observations that double strand breaks (DSBs) could produce unintended on- target outcomes in hematopoietic stem and progenitor cells (HSPCs) such as long deletions and centromere-distal chromosome fragment loss. We show these unintended outcomes are a byproduct of cellular proliferation stimulated by ex vivo culture. Editing HSPCs without cytokine culture bypassed long deletion and micronuclei formation while preserving efficient on-target editing and engraftment function. These results indicate that nuclease editing of quiescent hematopoietic stem cells (HSCs) limits DSB genotoxicity while maintaining therapeutic potency and encourages efforts for in vivo delivery of nucleases to HSCs.
    DOI:  https://doi.org/10.1101/2023.05.27.542323
  11. Blood Adv. 2023 Jun 05. pii: bloodadvances.2023010140. [Epub ahead of print]
    How I read an article that uses machine learning methods.
    Aziz Nazha, Olivier Elemento, Shannon K McWeeney, Moses Miles, Torsten Haferlach.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023010140
  12. bioRxiv. 2023 May 18. pii: 2023.05.15.540305. [Epub ahead of print]
    Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification.
    Cheryl A C Peretz, Vanessa E Kennedy, Anushka Walia, Cyrille L Delley, Andrew Koh, Elaine Tran, Iain C Clark, Corey E Hayford, Chris D'Amato, Yi Xue, Kristina M Fontanez, Ritu Roy, Aaron C Logan, Alexander E Perl, Adam Abate, Adam Olshen, Catherine C Smith.
      Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.
    DOI:  https://doi.org/10.1101/2023.05.15.540305
  13. Autophagy. 2023 Jun 08.
    Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
    Kristina Ames, Kira Gritsman.
      Myelodysplastic syndrome (MDS) is a clonal malignancy that develops from hematopoietic stem cells (HSCs), but the underlying mechanisms of MDS initiation are not well understood. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is often dysregulated in MDS. To investigate how PI3K inactivation affects HSC function, we generated a mouse model in which three Class IA PI3K genes were deleted in hematopoietic cells. Surprisingly, PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. PI3K-deficient HSCs had impaired autophagy, and pharmacologic treatment with autophagy-inducing reagents improved HSC differentiation. Furthermore, a similar autophagic degradation defect was observed in MDS patient HSCs. Therefore, our study uncovered a crucial protective role for Class IA PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation.
    Keywords:  Myelodysplastic syndrome; PI3K/AKT; autophagic flux; autophagosome; autophagy; differentiation; hematopoietic stem cells; lysosome; self-renewal
    DOI:  https://doi.org/10.1080/15548627.2023.2221922
  14. Nature. 2023 Jun 07.
    Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin.
    Gabriel K Griffin, Christopher A G Booth, Katsuhiro Togami, Sun Sook Chung, Daniel Ssozi, Julia A Verga, Juliette M Bouyssou, Yoke Seng Lee, Vignesh Shanmugam, Jason L Hornick, Nicole R LeBoeuf, Elizabeth A Morgan, Bradley E Bernstein, Volker Hovestadt, Peter van Galen, Andrew A Lane.
      Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1-4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
    DOI:  https://doi.org/10.1038/s41586-023-06156-8
  15. Blood Adv. 2023 Jun 05. pii: bloodadvances.2022009618. [Epub ahead of print]
    Secondary bile acids function through the vitamin D receptor in myeloid progenitors to promote myelopoiesis.
    Brandon Thompson, Shan Lu, Julio Revilla, Md Jashim Uddin, David N Oakland, Savannah Grace Brovero, Sunduz Keles, Emery H Bresnick, William A Petri, Stacey L Burgess.
      Metabolic products of the microbiota can alter hematopoiesis. However, the contribution and site of action of bile acids is poorly understood. Here we demonstrate that the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), increase bone marrow myelopoiesis. Treatment of bone marrow cells with DCA and LCA preferentially expanded immunophenotypic and functional (CFU-GM) granulocyte-monocyte progenitors (GMPs). DCA treatment of sorted hematopoietic stem/progenitor cells (HSPCs) increased CFU-GMs, indicating that direct exposure of HSPCs to DCA sufficed to increase GMPs. The vitamin D receptor (VDR) was required for the DCA-induced increase in CFU-GMs and GMPs. Single-cell RNA sequencing revealed that DCA significantly upregulated genes associated with myeloid differentiation and proliferation in GMPs. The action of DCA on HSPCs to expand GMPs in a VDR-dependent manner suggests microbiome-host interactions may directly impact bone marrow hematopoiesis and potentially the severity of infectious and inflammatory disease.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009618
  16. Blood. 2023 Jun 08. 141(23): 2793-2795
    Double, double, TP53, and trouble in myelofibrosis.
    Pramila Krishnamurthy.
      
    DOI:  https://doi.org/10.1182/blood.2023020421
  17. Hematology. 2023 Dec;28(1): 2220518
    Bridging to transplant and post-transplant maintenance therapy with FLT3 inhibitors in patients with relapsed or refractory FLT3 mutated acute myeloid leukemia.
    Natsuki Hirose, Takayoshi Tachibana, Akihiko Izumi, Shuku Sato, Noriyuki Tadera, Yotaro Tamai, Heiwa Kanamori, Masatsugu Tanaka, Hideaki Nakajima.
      OBJECTIVES AND METHODS: This single-center retrospective study was performed to evaluate the safety and efficacy of FMS-like tyrosine kinase 3 (FLT3) inhibitors before and after allogeneic hematopoietic cell transplantation (HCT) in relapsed/refractory patients with FLT3-mutation positive acute myeloid leukemia (AML).RESULTS: Ten patients who met the eligibility criteria were included. Eight of them achieved hematological remission at HCT, within a median span of 79 days (range: 43-197). In post-HCT, patients started maintenance therapy (MT; median time-to-start 79 days, range: 43-197), and the median duration of MT was 390 days (range: 67-815). Grade 3 hematological adverse events (AEs) were found in two patients, and non-hematological AEs were found in five patients. Nine patients underwent either dose reduction, discontinuation of therapy, or a switch to another FLT3 inhibitor due to AEs. Disease relapse occurred in one patient during MT. At the time of the last follow-up, seven patients are alive and disease-free, while three have died due to infection or transplant complications.
    CONCLUSION: In relapsed/refractory FLT3 mutation-positive AML, the use of FLT3 inhibitors can lead to high response rates and provide a safe bridge from HCT to MT. If sufficient attention is paid to safety, this therapy is expected to prevent disease relapse even with reduced dosages.
    Keywords:  Acute myeloblastic leukemia; FLT3 inhibitors; bridging; maintenance therapy; transplantation
    DOI:  https://doi.org/10.1080/16078454.2023.2220518
  18. J Clin Oncol. 2023 Jun 09. JCO2202699
    Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase-II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS).
    Esther Natalie Oliva, Marta Riva, Pasquale Niscola, Valeria Santini, Massimo Breccia, Valentina Giai, Antonella Poloni, Andrea Patriarca, Elena Crisà, Isabella Capodanno, Prassede Salutari, Gianluigi Reda, Nicola Cascavilla, Dario Ferrero, Attilio Guarini, Giovanni Tripepi, Giuseppe Iannì, Emilio Russo, Andrea Castelli, Bruno Fattizzo, Germana Beltrami, Monica Bocchia, Alfredo Molteni, Pierre Fenaux, Ulrich Germing, Alessandra Ricco, Giuseppe A Palumbo, Stefana Impera, Nicola Di Renzo, Flavia Rivellini, Francesco Buccisano, Aspasia Stamatoullas-Bastard, Anna Marina Liberati, Anna Candoni, Ilaria Maria Delfino, Maria Teresa Arcadi, Patrizia Cufari, Lorenzo Rizzo, Irene Bova, Maria Grazia D'Errigo, Gina Zini, Roberto Latagliata.
      PURPOSE: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia.METHODS: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 103/mm3) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 103/mm3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics.
    RESULTS: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.
    CONCLUSION: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
    DOI:  https://doi.org/10.1200/JCO.22.02699
  19. J Biol Chem. 2023 Jun 01. pii: S0021-9258(23)01905-1. [Epub ahead of print] 104877
    Loss of the mitochondrial protein Abcb10 results in altered arginine metabolism in MEL and K562 cells and nutrient stress signaling through ATF4.
    Marisa Miljkovic, Alexandra Seguin, Xuan Jia, James E Cox, Jonathan Leon Catrow, Hector Bergonia, John D Phillips, W Zac Stephens, Diane M Ward.
      Abcb10 is a mitochondrial membrane protein involved in hemoglobinization of red cells. Abcb10 topology and ATPase domain localization suggest it exports a substrate, likely biliverdin, out of mitochondria that is necessary for hemoglobinization. In this study we generated Abcb10 deletion cell lines in both mouse murine erythroleukemia (MEL) and human erythroid precursor human myelogenous leukemia (K562) cells to better understand the consequences of Abcb10 loss. Loss of Abcb10 resulted in an inability to hemoglobinize upon differentiation in both K562 and MEL cells with reduced heme and intermediate porphyrins and decreased levels of aminolevulinic acid synthase 2 activity. Metabolomic and transcriptional analyses revealed that Abcb10 loss gave rise to decreased cellular arginine levels, increased transcripts for cationic and neutral amino acid transporters with reduced levels of the citrulline to arginine converting enzymes argininosuccinate synthetase and argininosuccinate lyase. The reduced arginine levels in Abcb10 null cells gave rise to decreased proliferative capacity. Arginine supplementation improved both Abcb10 null proliferation and hemoglobinization upon differentiation. Abcb10 null cells showed increased phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2A), increased expression of nutrient sensing transcription factor ATF4 and downstream targets DNA damage inducible transcript 3 (Chop), ChaC glutathione specific gamma-glutamylcyclotransferase 1 (Chac1) and arginyl-tRNA synthetase 1 (Rars). These results suggest that when the Abcb10 substrate is trapped in the mitochondria, the nutrient sensing machinery is turned on remodeling transcription to block protein synthesis necessary for proliferation and hemoglobin biosynthesis in erythroid models.
    Keywords:  Arginine; differentiation; erythroid; metabolism; nutrient; transporter
    DOI:  https://doi.org/10.1016/j.jbc.2023.104877
  20. Blood. 2023 Jun 09. pii: blood.2022019333. [Epub ahead of print]
    Lipid Nanoparticles Allow Efficient and Harmless Ex Vivo Gene Editing of Human Hematopoietic Cells.
    Valentina Vavassori, Samuele Ferrari, Stefano Beretta, Claudia Asperti, Luisa Albano, Andrea Annoni, Chiara Gaddoni, Angelica Varesi, Monica Soldi, Alessandro Cuomo, Tiziana Bonaldi, Marina Radrizzani, Ivan Merelli, Luigi Naldini.
      Ex vivo gene editing in T cells and hematopoietic stem/progenitor cells (HSPCs) holds promise for treating diseases. Gene editing encompasses delivery of a programmable editor RNA or ribonucleoprotein, often achieved ex vivo by electroporation and, when aiming to homology-driven correction, of a DNA template often provided by viral vectors together with a nuclease editor. Whereas HSPCs activate robust p53-dependent DNA damage response (DDR) upon nuclease-based editing, the responses triggered in T cells remain poorly characterized. Here, we performed comprehensive multi-omics analyses and found that electroporation is the main culprit of cytotoxicity in T cells, causing death and cell cycle delay, perturbing metabolism and inducing inflammatory response. Nuclease RNA delivery by lipid nanoparticles (LNPs) nearly abolished cell death and ameliorated cell growth, improving tolerance to the procedure and yielding higher number of edited cells compared to electroporation. Transient transcriptomic changes upon LNP treatment were mostly caused by cellular loading with exogenous cholesterol, whose potentially detrimental impact could be overcome by limiting exposure. Notably, LNP-based HSPC editing dampened p53 pathway induction and supported higher clonogenic activity and similar or higher reconstitution by long-term repopulating HSPCs compared to electroporation, reaching comparable editing efficiencies. Overall, LNPs may allow efficient and harmless ex vivo gene editing in hematopoietic cells for treatment of human diseases.
    DOI:  https://doi.org/10.1182/blood.2022019333
  21. Blood Adv. 2023 Jun 08. pii: bloodadvances.2023010722. [Epub ahead of print]
    CNL and aCML are prognostically distinct: a large national cancer database analysis.
    Douglas Tremblay, Dahiel Sastow, John O Mascarenhas.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023010722
  22. Nature. 2023 Jun 07.
    Heritable transcriptional defects from aberrations of nuclear architecture.
    Stamatis Papathanasiou, Nikos A Mynhier, Shiwei Liu, Gregory Brunette, Ema Stokasimov, Etai Jacob, Lanting Li, Caroline Comenho, Bas van Steensel, Jason D Buenrostro, Cheng-Zhong Zhang, David Pellman.
      Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1-3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.
    DOI:  https://doi.org/10.1038/s41586-023-06157-7
  23. Nature. 2023 Jun 07.
    Epigenetic dysregulation from chromosomal transit in micronuclei.
    Albert S Agustinus, Duaa Al-Rawi, Bhargavi Dameracharla, Ramya Raviram, Bailey S C L Jones, Stephanie Stransky, Lorenzo Scipioni, Jens Luebeck, Melody Di Bona, Danguole Norkunaite, Robert M Myers, Mercedes Duran, Seongmin Choi, Britta Weigelt, Shira Yomtoubian, Andrew McPherson, Eléonore Toufektchan, Kristina Keuper, Paul S Mischel, Vivek Mittal, Sohrab P Shah, John Maciejowski, Zuzana Storchova, Enrico Gratton, Peter Ly, Dan Landau, Mathieu F Bakhoum, Richard P Koche, Simone Sidoli, Vineet Bafna, Yael David, Samuel F Bakhoum.
      Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.
    DOI:  https://doi.org/10.1038/s41586-023-06084-7
  24. Acta Biochim Biophys Sin (Shanghai). 2023 Jun 02.
    Immunotherapy in leukaemia.
    Xingmei Mu, Chumao Chen, Loujie Dong, Zhaowei Kang, Zhixian Sun, Xijie Chen, Junke Zheng, Yaping Zhang.
      Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has been made in basic research and preclinical studies for acute leukaemia compared to that of the many other types/subtypes of leukaemia, especially the exploration of the biological basis and application of immunotherapy in acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). In this review, we summarize the basic approaches to immunotherapy for leukaemia and focus on the research progress made in immunotherapy development for AML and ALL. Importantly, despite the advances made to date, big challenges still exist in the effectiveness of leukaemia immunotherapy, especially in AML. Therefore, we use AML as an example and summarize the mechanisms of tumour cell immune evasion, describe recently reported data and known therapeutic targets, and discuss the obstacles in finding suitable treatment targets and the results obtained in recent clinical trials for several types of single and combination immunotherapies, such as bispecific antibodies, cell therapies (CAR-T-cell treatment), and checkpoint blockade. Finally, we summarize novel immunotherapy strategies for treating lymphocytic leukaemia and clinical trial results.
    DOI:  https://doi.org/10.3724/abbs.2023101
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