bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024‒06‒30
29 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.
  2. Chronic TNF in the aging microenvironment exacerbates Tet2-loss-of-function myeloid expansion.
  3. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
  4. DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy.
  5. Oncogene induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.
  6. FLT3 inhibitor maintenance after allogeneic stem cell transplantation in FLT3-mutated acute myeloid leukemia (AML) patients.
  7. Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.
  8. Dotting out AML by targeting Fibrillarin.
  9. Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.
  10. The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance.
  11. Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy.
  12. Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated Acute Myeloid Leukemia (AML) to guide treatment strategy.
  13. IL-9 Secreted by Leukemia Stem Cells Induces Th1-Skewed CD4+ T-Cells, which Promote Their Expansion.
  14. Donor Types and Outcomes of Transplantation in Myelofibrosis: A CIBMTR Study.
  15. Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors.
  16. Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk.
  17. G2 arrest primes hematopoietic stem cells for megakaryopoiesis.
  18. Cerebrospinal fluid distribution and pharmacokinetics of ponatinib in Ph1-positive acute lymphoblastic leukemia.
  19. Utilizing Epigenetic Regulators to improve HSC-based lentiviral gene therapy.
  20. Response and Resistance to Menin Inhibitor in UBTF-Tandem Duplication AML.
  21. Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.
  22. How risky is a second allogeneic stem cell transplantation?
  23. The evolutionary journey from essential thrombocythaemia to acute erythroid leukaemia.
  24. Prognostic implications of ΔNp73/TAp73 expression ratio in core-binding factor acute myeloid leukemia.
  25. Monitoring molecular changes in the management of myelodysplastic syndromes.
  26. Recent advances in JAK2 inhibition for the treatment of myelofibrosis.
  27. Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.
  28. Complete absence of GLUT1 does not impair human terminal erythroid differentiation.
  29. Protocol to construct humanized mice with adult CD34+ hematopoietic stem and progenitor cells.
  1. Blood Adv. 2024 Jun 28. pii: bloodadvances.2024012858. [Epub ahead of print]
    Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.
    Jan Philipp Bewersdorf, Shai Shimony, Rory M Shallis, Yiwen Liu, Guillaume Berton, Eva Johanna Schaefer, Amer M Zeidan, Aaron D Goldberg, Eytan M Stein, Guido Marcucci, Rebecca Bystrom, R Coleman Lindsley, Evan C Chen, Jorge Miguel Ramos Perez, Anthony S Stein, Vinod A Pullarkat, Ibrahim Aldoss, Daniel J DeAngelo, Donna S Neuberg, Richard M Stone, Sylvain Garciaz, Brian J Ball, Maximilian Stahl.
      While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).
    DOI:  https://doi.org/10.1182/bloodadvances.2024012858
  2. Blood Adv. 2024 Jun 26. pii: bloodadvances.2023011833. [Epub ahead of print]
    Chronic TNF in the aging microenvironment exacerbates Tet2-loss-of-function myeloid expansion.
    Candice Quin, Erica N DeJong, Amy Jm McNaughton, Marco M Buttigieg, Salman Basrai, Sagi Abelson, Margaret Larche, Michael J Rauh, Dawn Me Bowdish.
      Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cell (HSC) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing TNF favours TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2-mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- genotypes reconstituted with WT CD45.1+ and Tet2-/-CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2-/-cells in old WT recipient mice, with strong skewing towards the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- recipient mice, suggesting that TNF signalling is essential for the expansion Tet2-mutant myeloid clones. Examination of human rheumatoid arthritis patients with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011833
  3. Cell Stem Cell. 2024 Jun 19. pii: S1934-5909(24)00207-8. [Epub ahead of print]
    Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
    Niels Asger Jakobsen, Sven Turkalj, Andy G X Zeng, Bilyana Stoilova, Marlen Metzner, Susann Rahmig, Murtaza S Nagree, Sayyam Shah, Rachel Moore, Batchimeg Usukhbayar, Mirian Angulo Salazar, Grigore-Aristide Gafencu, Alison Kennedy, Simon Newman, Benjamin J L Kendrick, Adrian H Taylor, Rasheed Afinowi-Luitz, Roger Gundle, Bridget Watkins, Kim Wheway, Debra Beazley, Alex Murison, Alicia G Aguilar-Navarro, Eugenia Flores-Figueroa, Stephanie G Dakin, Andrew J Carr, Claus Nerlov, John E Dick, Stephanie Z Xie, Paresh Vyas.
      Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.
    Keywords:  DNMT3A; TET2; aging; clonal competition; clonal hematopoiesis; hematopoietic stem cells; single-cell RNA-seq; single-cell genomics; somatic mosaicism
    DOI:  https://doi.org/10.1016/j.stem.2024.05.010
  4. Leukemia. 2024 Jun 27.
    DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy.
    Emily Stepanchick, Andrew Wilson, Analise M Sulentic, Kwangmin Choi, Kathleen Hueneman, Daniel T Starczynowski, Timothy M Chlon.
      Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
    DOI:  https://doi.org/10.1038/s41375-024-02304-9
  5. J Clin Invest. 2024 Jun 25. pii: e177460. [Epub ahead of print]
    Oncogene induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.
    Nana Talvard-Balland, Lukas M Braun, Karen O Dixon, Melissa Zwick, Helena Engel, Alina Hartmann, Sandra Duquesne, Livius Penter, Geoffroy Andrieux, Lukas Simon Rindlisbacher, Andrea Acerbis, Jule Ehmann, Christoph Köllerer, Michela Ansuinelli, Andres Rettig, Kevin Moschallski, Petya Apostolova, Tilman Brummer, Anna L Illert, Markus A Schramm, Yurong Cheng, Anna Köttgen, Justus Duyster, Hans D Menssen, Jerome Ritz, Bruce R Blazar, Melanie Boerries, Annette Schmitt Graeff, Nurefsan Sariipek, Peter van Galen, Joerg M Buescher, Nina Cabezas-Wallscheid, Heike L Pahl, Erika L Pearce, Robert J Soiffer, Catherine J Wu, Luca Vago, Burkhard Becher, Natalie Köhler, Tobias Wertheimer, Vijay K Kuchroo, Robert Zeiser.
      Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting TIM-3 for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab-treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment-resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ T cells (Tc) enhanced Tc activation, proliferation and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3-treatment-mediated GVL effects are Tc-induced. In contrast to anti-PD-1 and anti-CTLA-4-treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host-disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We deciphered the connection between oncogenic mutations found in AML and TIM-3 ligands expression and identify anti-TIM-3-treatment as a strategy to enhance GVL effects via metabolic and transcriptional Tc-reprogramming, without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Abs in patients with AML relapse post-allo-HCT.
    Keywords:  Bone marrow transplantation; Transplantation
    DOI:  https://doi.org/10.1172/JCI177460
  6. Ann Transl Med. 2024 Jun 10. 12(3): 49
    FLT3 inhibitor maintenance after allogeneic stem cell transplantation in FLT3-mutated acute myeloid leukemia (AML) patients.
    Gong He, Erika Belmont, Theodore Karrison, Wendy Stock, James L LaBelle, Satyajit Kosuri, Richard A Larson, Justin P Kline, Peter A Riedell, Mariam Nawas, Michael R Bishop, Hongtao Liu.
      Background: The somatic mutation of fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is associated with increased risk of relapse and lower survival rates. FLT3i as maintenance after allogeneic hematopoietic stem cell transplant (allo-HSCT) are under study to prevent disease relapse, but real-world data are lacking.Methods: We performed a single center, retrospective cohort study and analyzed patients who had FLT3-mutated AML and underwent allogeneic-HSCT between January 2011 to June 2022 at the University of Chicago. We identified 23 patients who received FLT3i maintenance therapy post-allo-HSCT and compared their outcomes against 57 patients who did not. Primary outcome was disease-free survival (DFS). Secondary outcomes include overall survival (OS) and relapse rate.
    Results: FLT3i maintenance therapy was started at a median 59 days (range, 29-216 days) after allo-HSCT with median duration of 287 days (range, 15-1,194 days). Maintenance therapy was well tolerated. Overall, the improvement in DFS rates for patients after they were placed on FLT3i maintenance therapy was not significant [hazard ratio (HR) for relapse or death =0.65, 95% confidence interval (CI): 0.32-1.31, P=0.23]. However, when adjusted for the conditioning regimen and donor status, the differences were statistically significant with improvement in DFS and OS for patients on FLT3i maintenance (HR for OS =0.42, 95% CI: 0.18-0.95, P=0.04).
    Conclusions: When adjusting for conditioning regimen and donor status, there was a significant improvement in DFS and OS for patients who received FLT3i maintenance therapy compared to those who did not. Randomized prospective studies may provide more insight.
    Keywords:  FLT3 inhibitor (FLT3i); Fms-like tyrosine kinase 3 (FLT3); acute myeloid leukemia (AML); maintenance; relapse
    DOI:  https://doi.org/10.21037/atm-23-1941
  7. Genomics Proteomics Bioinformatics. 2024 Jun 24. pii: qzae049. [Epub ahead of print]
    Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.
    Weidong Liu, Yuhua Wang, Shuxin Yao, Guoqiang Han, Jin Hu, Rong Yin, Fuling Zhou, Ying Cheng, Haojian Zhang.
      Hematopoietic homeostasis is maintained by hematopoietic stem cells (HSCs), and it is tightly controlled at multiple levels to sustain the self-renewal capacity and differentiation potential of HSCs. Dysregulation of self-renewal and differentiation of HSCs leads to the development of hematologic diseases, including acute myeloid leukemia (AML). Thus, understanding the underlying mechanisms of HSC maintenance and the development of hematologic malignancies is one of the fundamental scientific endeavors in stem cell biology. N  6-methyladenosine (m6A) is a common modification in mammalian messenger RNAs (mRNAs) and plays important roles in various biological processes. In this study, we performed a comparative analysis of the dynamics of the RNA m6A methylome of hematopoietic stem and progenitor cells (HSPCs) and leukemia-initiating cells (LICs) in AML. We found that RNA m6A modification regulates the transformation of long-term HSCs into short-term HSCs and determines the lineage commitment of HSCs. Interestingly, m6A modification leads to reprogramming that promotes cellular transformation during AML development, and LIC-specific m6A targets are recognized by different m6A readers. Moreover, the very long chain fatty acid transporter ATP-binding cassette subfamily D member 2 (ABCD2) is a key factor that promotes AML development, and deletion of ABCD2 damages clonogenic ability, inhibits proliferation, and promotes apoptosis of human leukemia cells. This study provides a comprehensive understanding of the role of m6A in regulating cell state transition in normal hematopoiesis and leukemogenesis, and identifies ABCD2 as a key factor in AML development.
    Keywords:  ATP-binding cassette subfamily D member 2; Acute myeloid leukemia; Hematopoiesis; Leukemia initiating cells; RNA m6A modification
    DOI:  https://doi.org/10.1093/gpbjnl/qzae049
  8. Cancer Res. 2024 Jun 26.
    Dotting out AML by targeting Fibrillarin.
    Hanzhi Luo, Michael G Kharas.
      Dysregulated biomolecular condensates, formed through multivalent interactions among proteins and nucleic acids have been recently identified to drive tumorigenesis. In acute myeloid leukemia (AML), condensates driven by RNA-binding proteins (RBPs) alter transcriptional networks. Yang and colleagues performed a CRISPR screen and identified Fibrillarin (FBL) as a new driver in AML leukemogenesis. FBL depletion caused cell cycle arrest and death in AML cells, with minimal impact on normal cells. FBL's phase separation domains are essential for pre-rRNA processing, influencing AML cell survival by regulating ribosome biogenesis and the translation of oncogenic proteins like MYC. Therapeutically, the chemotherapeutic agent CGX-635 targets FBL, inducing its aggregation, impairing pre-rRNA processing, and reducing AML cell survival. This highlights FBL's phase separation as a therapeutic vulnerability in AML. These findings suggest that targeting the phase separation properties of RBPs could offer a novel and effective strategy for AML treatment. Further research into condensate dynamics in cancer and development of condensate-modulating drugs holds significant promise for future cancer therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2125
  9. Haematologica. 2024 Jun 27.
    Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.
    Mohd Minhajuddin, Amanda Winters, Haobin Ye, Shanshan Pei, Brett Stevens, Austin Gillen, Krysta Engel, Stephanie Gipson, Monica Ransom, Maria Amaya, Anagha Inguva, Maura Gasparetto, Mark J Althoff, Regan Miller, Ian Shelton, Hunter Tolison, Anna Krug, Rachel Culp-Hill, Angelo D'Alessandro, Daniel W Sherbenou, Daniel A Pollyea, Clayton Smith, Craig T Jordan.
      The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.
    DOI:  https://doi.org/10.3324/haematol.2023.284716
  10. Leukemia. 2024 Jun 28.
    The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance.
    Haiyang Yun, Julian Zoller, Fengbiao Zhou, Christian Rohde, Yi Liu, Maximilian Felix Blank, Stefanie Göllner, Carsten Müller-Tidow.
      RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.
    DOI:  https://doi.org/10.1038/s41375-024-02322-7
  11. Leukemia. 2024 Jun 22.
    Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy.
    Céline Philippe, Manon Jaud, Kelly Féral, Alexandre Gay, Loïc Van Den Berghe, Manon Farce, Marina Bousquet, Stéphane Pyronnet, Laurent Mazzolini, Kevin Rouault-Pierre, Christian Touriol.
      Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell's viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.
    DOI:  https://doi.org/10.1038/s41375-024-02321-8
  12. Crit Rev Oncol Hematol. 2024 Jun 23. pii: S1040-8428(24)00167-7. [Epub ahead of print] 104424
    Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated Acute Myeloid Leukemia (AML) to guide treatment strategy.
    Martina Ruglioni, Stefania Crucitta, Giovanna Irene Luculli, Gaspare Tancredi, Maria Livia Del Giudice, Sandra Mechell, Sara Galimberti, Romano Danesi, Marzia Del Re.
      The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by Acute Myeloid Leukemia (AML). In this setting, in recent years, new FLT3-inhibitors have demonstrated efficacy in improving survival and treatment response. Nevertheless, the development of primary and secondary mechanisms of resistance poses a significant obstacle to their efficacy. Understanding these mechanisms is crucial for developing novel therapeutic approaches to overcome resistance and improve the outcomes of patients. In this context, the use of novel FLT3 inhibitors and the combination of different targeted therapies have been studied. This review provides an update on the molecular alterations involved in FLT3 AML mechanisms of resistance, exploring how the molecular monitoring may be used to guide treatment strategy in FLT3-mutated AML.
    Keywords:  Acute myeloid leukemia; FLT3 inhibitors; FLT3 mutation; mechanisms of resistance
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104424
  13. Blood. 2024 Jun 28. pii: blood.2024024000. [Epub ahead of print]
    IL-9 Secreted by Leukemia Stem Cells Induces Th1-Skewed CD4+ T-Cells, which Promote Their Expansion.
    Ramin Radpour, Cedric Simillion, Bofei Wang, Hussein A Abbas, Carsten Riether, Adrian Franz Ochsenbein.
      In acute myeloid leukemia (AML), leukemia stem and progenitor cells (LSCs and LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T-cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T-cells in the BM of AML patients were activated and skewed towards Th1-polarization whereas IL-9 producing (Th9) CD4+ T-cells were absent. In contrast to normal hematopoietic stem cells (HSCs), LSCs produced IL-9 and the correlation modelling predicted IL9 in LSCs as a main hub-gene that activates CD4+ T-cells in AML. Functional validation revealed that IL-9R signaling in CD4+ T-cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A, KMT2C genes resulting in methylation on histone H3 at lysine 4 (H3K4) to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation and effector cytokine secretion, including interferon (IFN)-ɣ and tumor necrosis factor (TNF)-α. IFN-ɣ and to a lesser extend TNF-α produced by activated CD4+ T-cells, induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF and IFNG expression in BM-infiltrating CD4+ T-cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-ɣ and TNF-α.
    DOI:  https://doi.org/10.1182/blood.2024024000
  14. Blood Adv. 2024 Jun 25. pii: bloodadvances.2024013451. [Epub ahead of print]
    Donor Types and Outcomes of Transplantation in Myelofibrosis: A CIBMTR Study.
    Tania Jain, Noel Estrada-Merly, M Queralt Salas, Soyoung Kim, Jakob D DeVos, Min Chen, Xi Fang, Rajat Kumar, Marcio Andrade-Campos, Hany Elmariah, Vaibhav Agrawal, Mahmoud Aljurf, Ulrike Bacher, Talha Badar, Sherif M Badawy, Karen Kuhn Ballen, Amer Beitinjaneh, Vijaya R Bhatt, Christopher N Bredeson, Zachariah DeFilipp, Bhagirathbhai Dholaria, Nosha Farhadfar, Shatha Farhan, Arpita Gandhi, Siddhartha Ganguly, Usama Gergis, Michael R Grunwald, Nada Hamad, Betty K Hamilton, Yoshihiro Inamoto, Madiha Iqbal, Omer Jamy, Mark Juckett, Mohamed A Kharfan-Dabaja, Maxwell M Krem, Deepesh P Lad, Jane L Liesveld, Monzr M Al Malki, Adriana K Malone, Hemant S Murthy, Guillermo Ortí, Sagar S Patel, Attaphol Pawarode, Miguel-Angel Perales, Marjolein W M van der Poel, Olle Ringden, David A Rizzieri, Alicia Rovo, Bipin N Savani, Mary Lynn Savoie, Sachiko Seo, Melhem M Solh, Celalettin Ustun, Leo F Verdonck, John R Wingard, Baldeep Wirk, Nelli Bejanyan, Richard J Jones, Taiga Nishihori, Betul Oran, Ryotaro Nakamura, Bart L Scott, Wael Saber, Vikas Gupta.
      We aim to evaluate impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using CIBMTR registry data for HCTs done between 2013 and 2019. In all 1597 undergoing HCT for myelofibrosis, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study eligible, 1032 patients who received peripheral blood grafts for chronic phase myelofibrosis, 38% recipients of haploidentical-HCT were of non-White/Caucasian ethnicity. Matched sibling donor (MSD)-HCTs were independently associated with superior overall survival (OS) in the first 3 months [reference MSD, haploidentical HR 5.80 (95% CI 2.52-13.35), matched unrelated HR 4.50 (95% CI 2.24-9.03), and mismatched unrelated HR 5.13 (95% CI 1.44-18.31), P<0.001]. This difference in OS aligns with lower graft failure with MSD [haploidentical HR 6.11 (95%CI 2.98-12.54), matched unrelated HR 2.33 (95%CI 1.20-4.51), mismatched unrelated HR 1.82 (95%CI 0.58-5.72). There was no significant difference in OS among haploidentical, matched unrelated, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months post-HCT, relapse, disease-free survival or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. While MSDs remain a superior donor option due to improved engraftment, there is no significant difference in HCT outcomes from haploidentical and matched unrelated donors. These results establish haploidentical-HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013451
  15. Transplant Cell Ther. 2024 Jun 22. pii: S2666-6367(24)00481-0. [Epub ahead of print]
    Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors.
    Eduardo Rodríguez-Arbolí, Megan Othus, Corentin Orvain, Naveed Ali, Filippo Milano, Chris Davis, Ryan Basom, Domitilla Baccon, Brenda M Sandmaier, Frederick R Appelbaum, Roland B Walter.
      BACKGROUND: Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with AML or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized.OBJECTIVES: To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and non-relapse mortality (NRM).
    STUDY DESIGN: We studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n=73) or MDS/AML (n=8).
    RESULTS: With a median follow-up among survivors of 74.0 (range: 10.4-187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27-48%), 32% (23-44%), and 35% (26-47%). The rate of NRM at 100 days and 18 months was 20% (12-29%) and 28% (19-39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (i.e. morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or Treatment-Related Mortality (TRM) score. After multivariable adjustment, active disease was associated with a higher risk of relapse (HR=3.19, p=0.006) and shorter RFS (HR=2.41, p=0.008) as well as OS (HR=2.17, p=0.027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease (MRD). Similarly, a relapse-free interval <6 months after the first allograft was associated with higher risk of relapse (HR=5.86, p<0.001) and shorter RFS (HR=2.86; p=0.001) and OS (HR=2.45, p=0.003). Additionally, a high HCT-CI score was associated with increased NRM (HR=4.30, p=0.035), and shorter RFS (HR=3.87, p=0.003) and OS (HR=3.74, p=0.006). Likewise, higher TRM scores were associated with increased risk of relapse (HR=2.27; p=0.024) and NRM (HR=2.01, p=0.001), and inferior RFS (HR=1.90 p=0.001) and OS (HR=1.88, p=0.001).
    CONCLUSIONS: A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.
    Keywords:  Acute Myeloid Leukemia; Allogeneic hematopoietic cell transplantation; Non-relapse mortality; measurable residual disease
    DOI:  https://doi.org/10.1016/j.jtct.2024.06.019
  16. Cancer Discov. 2024 Jun 25.
    Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk.
    Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Polonen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A de Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah Elisa Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean Hui Chiew, Tanya Khan, Michal Kicinski, Stefan Kohrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne Vibeke Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczen, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen Ej Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan.
      Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (yo T-ALL) is a poorly understood disease. We studied 200 children with yo T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. yo T-ALL diagnosed in children under three years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by Poly(ADP-ribose) polymerase (PARP) inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric yo T-ALL.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1452
  17. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00716-2. [Epub ahead of print]43(7): 114388
    G2 arrest primes hematopoietic stem cells for megakaryopoiesis.
    Corey M Garyn, Oriol Bover, John W Murray, Jing Ma, Karen Salas-Briceno, Susan R Ross, Hans-Willem Snoeck.
      In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is unclear, however. Here, we show that DNA damage induces MK markers in HSCs and that G2 arrest, an integral part of the DNA damage response, suffices for MK priming followed by irreversible MK differentiation in HSCs, but not in progenitors. We also show that replication stress causes DNA damage in HSCs and is at least in part due to uracil misincorporation in vitro and in vivo. Consistent with this notion, thymidine attenuated DNA damage, improved HSC maintenance, and reduced the generation of CD41+ MK-committed HSCs. Replication stress and concomitant MK differentiation is therefore one of the barriers to HSC maintenance. DNA damage-induced MK priming may allow rapid generation of a lineage essential to immediate organismal survival, while also removing damaged cells from the HSC pool.
    Keywords:  CP: Molecular biology; CP: Stem cell research; DNA damage; G2-arrest; direct megakarypoiesis; hematopoietic stem cells; hyperploidy; megakaryocytes
    DOI:  https://doi.org/10.1016/j.celrep.2024.114388
  18. Blood. 2024 Jun 25. pii: blood.2024024838. [Epub ahead of print]
    Cerebrospinal fluid distribution and pharmacokinetics of ponatinib in Ph1-positive acute lymphoblastic leukemia.
    Pierre Walczak, Sofiane Fodil, Nicolas Vignal, Aurelie Cabannes-Hamy, Nicolas Boissel, Emmanuel Raffoux, Jean-Michel Cayuela, Lauriane Goldwirt, Etienne Lengliné.
      Tyrosine kinase inhibitors have improved outcomes in Philadelphia-positive ALL, but their efficacy in CNS disease remains uncertain. Ponatinib was studied for CNS distribution in 22 samples from 16 patients. CSF concentrations fell below the 40nM threshold, suggesting suboptimal CNS exposure.
    DOI:  https://doi.org/10.1182/blood.2024024838
  19. Blood Adv. 2024 Jun 25. pii: bloodadvances.2024013047. [Epub ahead of print]
    Utilizing Epigenetic Regulators to improve HSC-based lentiviral gene therapy.
    Parisa Tajer, Emin Onur Karakaslar, Kirsten Canté-Barrett, Brigitta Naber, Sandra Vloemans, Marja van Eggermond, Marie-Louise van der Hoorn, Erik B van den Akker, Karin Pike-Overzet, Frank Jt Staal.
      Curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven for various diseases. However, the low number of true HSCs that can be collected from patients and subsequently in vitro maintenance and expansion of true HSCs for genetic correction remain challenging. Addressing this issue, we here focused on optimizing culture conditions to improve the ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explore the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The HDAC inhibitor Quisinostat and the bromodomain inhibitor CPI203 each promote ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single cell RNA-sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, while addition of Quisinostat or CPI203 improved expansion of HSCs in transduction protocols. Of note, we demonstrated that addition of Quisinostat improved LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effect of epigenetic regulators in hematopoietic stem cell biology and their clinical applications to advance HSC-based gene correction.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013047
  20. N Engl J Med. 2024 Jun 27. 390(24): 2323-2325
    Response and Resistance to Menin Inhibitor in UBTF-Tandem Duplication AML.
    Ing Soo Tiong, David S Ritchie, Piers Blombery.
      
    DOI:  https://doi.org/10.1056/NEJMc2404110
  21. Haematologica. 2024 Jun 27.
    Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.
    Yunfan Yang, Yuntao Liu, Hui Sun, Li Meng, Hai Lin, Chunyan Chen, Jianda Hu, Xuliang Shen, Minghui Duan, Yanli Zhang, Dilinazi Abulaiti, Jinghua Wang, Hongqian Zhu, Luoming Hua, Qing Leng, Chun Zhang, Lili Sun, Weiming Li, Huanling Zhu, Bingcheng Liu, Jianxiang Wang.
      To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.
    DOI:  https://doi.org/10.3324/haematol.2023.284892
  22. Leukemia. 2024 Jun 25.
    How risky is a second allogeneic stem cell transplantation?
    Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Nicolaus Kröger, Robert Zeiser, Fabio Ciceri, Thomas Schroeder, Peter Dreger, Jakob Passweg, Johannes Schetelig, Matthias Stelljes, Igor Wolfgang Blau, Georg-Nikolaus Franke, Katarina Riesner, Hélène Schoemans, Ivan Moiseev, Zinaida Peric.
      There is no consensus on second allogeneic stem cell transplantation (alloSCT) indications in patients with hematologic malignancies relapsing after a first alloSCT. In historic publications, a very high non-relapse mortality (NRM) has been described, arguing against performing a second alloSCT. We analysed the outcome of 3356 second alloSCTs performed 2011-21 following a hematologic malignancy relapse. Outcomes at two years after second alloSCT were: NRM 22%, relapse incidence 50%, overall survival 38%, and progression-free survival 28%. Key risk factors for increased NRM were: older age, low performance score, high disease-risk-index, early relapse after the first alloSCT, unrelated/haploidentical donor, and GVHD before second alloSCT. Any type of GVHD after first alloSCT was also important risk factor for acute GVHD and chronic GVHD after second alloSCT. There was a preferential use of a different donor (80%) at second alloSCT from first alloSCT. However, in multivariate analysis, the use of the same alloSCT donor for second alloSCT vs. a different donor was not associated with any of the survival or GVHD endpoints. We show considerably improved outcome as compared to historic reports. These current data support a wider use of second alloSCT and provide risk factors for NRM that need to be considered.
    DOI:  https://doi.org/10.1038/s41375-024-02318-3
  23. Lancet Haematol. 2024 Jul;pii: S2352-3026(24)00134-0. [Epub ahead of print]11(7): e550
    The evolutionary journey from essential thrombocythaemia to acute erythroid leukaemia.
    Oscar Borsani, Emanuela Boveri, Giacomo Riccaboni, Erica Travaglino, Daniela Pietra, Elisa Rumi.
      
    DOI:  https://doi.org/10.1016/S2352-3026(24)00134-0
  24. Blood Cancer J. 2024 Jun 24. 14(1): 102
    Prognostic implications of ΔNp73/TAp73 expression ratio in core-binding factor acute myeloid leukemia.
    Maria L Salustiano-Bandeira, Amanda Moreira-Aguiar, Diego A Pereira-Martins, Juan L Coelho-Silva, Isabel Weinhäuser, Pedro L França-Neto, Aleide S Lima, Ana S Lima, Anemari R Baccarin, Fernanda B Silva, Manuela A de Melo, Fernanda S Niemann, Luciana Nardinelli, César A Ortiz Rojas, Bruno K Duarte, Aderson S Araujo, Elisa A Azevedo, Clarice N Morais, Lorena L Figueiredo-Pontes, Jan J Schuringa, Gerwin Huls, Israel Bendit, Eduardo M Rego, Sara T Olalla Saad, Fabiola Traina, Marcos A Bezerra, Antonio R Lucena-Araujo.
      
    DOI:  https://doi.org/10.1038/s41408-024-01086-8
  25. Br J Haematol. 2024 Jun 27.
    Monitoring molecular changes in the management of myelodysplastic syndromes.
    Nicolas Duployez, Claude Preudhomme.
      The ongoing or anticipated therapeutic advances as well as previous experience in other malignancies, including acute myeloid leukaemia, have made molecular monitoring a potential interesting tool for predicting outcomes and demonstrating treatment efficacy in patients with myelodysplastic syndromes (MDS). The important genetic heterogeneity in MDS has made challenging the establishment of recommendations. In this context, high-throughput/next-generation sequencing (NGS) has emerged as an attractive tool, especially in patients with high-risk diseases. However, its implementation in clinical practice still suffers from a lack of standardization in terms of sensitivity, bioinformatics and result interpretation. Data from literature, mostly gleaned from retrospective cohorts, show NGS monitoring when used appropriately could help clinicians to guide therapy, detect early relapse and predict disease evolution. Translating these observations into personalized patient management requires a prospective evaluation in clinical research and remains a major challenge for the next years.
    Keywords:  measurable residual disease (MRD); myelodysplastic syndromes (MDS); next‐generation sequencing (NGS)
    DOI:  https://doi.org/10.1111/bjh.19614
  26. Expert Opin Pharmacother. 2024 Jun 26.
    Recent advances in JAK2 inhibition for the treatment of myelofibrosis.
    Noa Rippel, Marina Kremyanskaya.
      INTRODUCTION: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, cytopenias, a potential for leukemic transformation, and increased mortality. Patients who are ineligible for stem cell transplant rely on pharmacologic therapies of noncurative intent, whose cornerstone consists of JAK inhibitors (JAKi). While current JAKi are efficacious in controlling symptoms and splenic volume, none meaningfully reduce clonal burden nor halt disease progression, and patients oftentimes develop JAKi intolerant, relapsed, or refractory MF. As such, there remains an urgent necessity for second-line options and novel therapies with disease-modifying properties.AREAS COVERED: In this review, we delineate the mechanistic rationale, along with the latest safety and efficacy data, of investigational JAKi-based MF treatment strategies, with a focus on JAKi monotherapies and combinations of novel agents with approved JAKi. Our literature search consisted of extensive review of PubMed and clinicaltrials.gov.
    EXPERT OPINION: A myriad of promising MF-directed therapies are in late-phase studies. Following their approval, treatment selection should be tailored to patient-specific treatment goals and disease characteristics, with an emphasis on combination therapies of JAKi with novel agents of differing mechanistic targets that possess anti-clonal properties, in attempt to alter disease course and concurrently limit dose-dependent JAKi toxicities.
    Keywords:  JAK inhibitors; myelofibrosis; myeloproliferative neoplasm
    DOI:  https://doi.org/10.1080/14656566.2024.2372453
  27. Mol Oncol. 2024 Jun 22.
    Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.
    Huan Li, Zhijie Cao, Yiming Liu, Zhenya Xue, Yishuang Li, Haiyan Xing, Yingxi Xu, Runxia Gu, Shaowei Qiu, Hui Wei, Min Wang, Qing Rao, Jianxiang Wang.
      Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell-tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label-retaining slow-cycling leukemia cell population from AML1-ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH-staining, a higher proportion of PKH-retaining cells are in G0 phase, and PKH-retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH-retaining cells possess high chemo-resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH-retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin-CD74- leukemia cells, Lin-CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow-cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.
    Keywords:  CD74; acute myeloid leukemia; chemotherapy resistance; leukemia stem cell; quiescence; self‐renewal
    DOI:  https://doi.org/10.1002/1878-0261.13690
  28. Blood Adv. 2024 Jun 25. pii: bloodadvances.2024012743. [Epub ahead of print]
    Complete absence of GLUT1 does not impair human terminal erythroid differentiation.
    Catarina Martins Freire, Nadine R King, Monika Dzieciatkowska, Daniel Stephenson, Pedro Luis Moura, Johannes Dobbe, Geert Streekstra, Angelo D'Alessandro, Ashley Mark Toye, Timothy J Satchwell.
      The Glucose transporter 1 (GLUT1) is one of the most abundant proteins within the erythrocyte membrane and is required for glucose and dehydroascorbic acid (Vitamin C precursor) transport. It is widely recognized as a key protein for red cell structure, function, and metabolism. Previous reports highlighted the importance of GLUT1 activity within these uniquely glycolysis-dependent cells, in particular for increasing antioxidant capacity needed to avoid irreversible damage from oxidative stress in humans. However, studies of glucose transporter roles in erythroid cells are complicated by species-specific differences between humans and mice. Here, using CRISPR-mediated gene editing of immortalized erythroblasts and adult CD34+ hematopoietic progenitor cells, we generate committed human erythroid cells completely deficient in expression of GLUT1. We show that absence of GLUT1 does not impede human erythroblast proliferation, differentiation, or enucleation. This work demonstrates for the first-time generation of enucleated human reticulocytes lacking GLUT1. The GLUT1-deficient reticulocytes possess no tangible alterations to membrane composition or deformability in reticulocytes. Metabolomic analyses of GLUT1-deficient reticulocytes reveal hallmarks of reduced glucose import, downregulated metabolic processes and upregulated AMPK-signalling, alongside alterations in antioxidant metabolism, resulting in increased osmotic fragility and metabolic shifts indicative of higher oxidant stress. Despite detectable metabolic changes in GLUT1 deficient reticulocytes, the absence of developmental phenotype, detectable proteomic compensation or impaired deformability comprehensively alters our understanding of the role of GLUT1 in red blood cell structure, function and metabolism. It also provides cell biological evidence supporting clinical consensus that reduced GLUT1 expression does not cause anaemia in GLUT1 deficiency syndrome.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012743
  29. STAR Protoc. 2024 Jun 26. pii: S2666-1667(24)00320-4. [Epub ahead of print]5(3): 103155
    Protocol to construct humanized mice with adult CD34+ hematopoietic stem and progenitor cells.
    Chun I Yu, Rick Maser, Florentina Marches, Jacques Banchereau, Karolina Palucka.
      Humanized mice, defined as mice with human immune systems, have become an emerging model to study human hematopoiesis, infectious disease, and cancer. Here, we describe the techniques to generate humanized NSGF6 mice using adult human CD34+ hematopoietic stem and progenitor cells (HSPCs). We describe steps for constructing and monitoring the engraftment of humanized mice. We then detail procedures for tissue processing and immunophenotyping by flow cytometry to evaluate the multilineage hematopoietic differentiation. For complete details on the use and execution of this protocol, please refer to Yu et al.1.
    Keywords:  Flow Cytometry; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2024.103155
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