bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–12–08
thirty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Impact of Measurable Residual Disease Clearance Kinetics in Patients with AML Undergoing Intensive Chemotherapy.
  2. The dynamics of hematopoiesis over the human lifespan.
  3. Honing CAR T cells to tackle acute myeloid leukemia.
  4. FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML.
  5. Evolution of myeloproliferative neoplasms from normal blood stem cells.
  6. Clinical perspectives on post-induction maintenance therapy in patients with acute myeloid leukaemia in remission who are ineligible for allogeneic haematopoietic stem cell transplantation.
  7. Is there really an accelerated phase of chronic myeloid leukaemia at presentation?
  8. Advantages of a genomic DNA-based NGS assay for detection of mutant NPM1 measurable residual disease in AML.
  9. Single cell multiomics reveal divergent effects of DNMT3A and TET2 mutant clonal hematopoiesis in inflammatory response.
  10. Does size matter? Center-specific characteristics and survival after allogeneic hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry for Stem Cell Transplantation and Cell Therapy.
  11. Genetic and environmental risks for clonal hematopoiesis and cancer.
  12. TIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A.
  13. Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety.
  14. Pathogenesis and management of high molecular risk myeloproliferative neoplasms.
  15. HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia.
  16. Trial eligibility, treatment patterns and outcome for venetoclax-based therapy in AML: a prospective cohort study.
  17. Survival impact of hypoxia-inducible factor-1 alpha (HIF-1α) in Nucleophosmin1 mutated acute myeloid leukemia.
  18. Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.
  19. High iASPP (PPP1R13L) expression is an independent predictor of adverse clinical outcome in acute myeloid leukemia (AML).
  20. Treatment of high risk myelodysplastic syndrome.
  21. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
  22. How to improve AML outcomes?
  23. Age-related clonal hematopoiesis and HIV infection are associated with geriatric outcomes: The ARCHIVE study.
  24. CD33-CD123 IF-THEN gating reduces toxicity while enhancing the specificity and memory phenotype of AML-targeting CAR-T cells.
  25. Clonal hematopoiesis of indeterminate potential (CHIP) and its association with treatment outcomes and adverse events in patients with solid tumours.
  26. Fetal hepatocytes protect the HSPC genome via fetuin-A.
  27. Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.
  28. Venetoclax-Proteasome inhibitor-Dexamethasone for unfit patients with Blastic Plasmacytoid Dendritic Cell Neoplasm.
  29. FDA approves first menin inhibitor, for acute leukaemia.
  30. Global Disparities in the Characteristics and Outcomes of Leukemia Clinical Trials: A Cross-Sectional Study of the ClinicalTrials.gov Database.
  1. Blood Adv. 2024 Dec 04. pii: bloodadvances.2024013826. [Epub ahead of print]
    Impact of Measurable Residual Disease Clearance Kinetics in Patients with AML Undergoing Intensive Chemotherapy.
    Wei Ying Jen, Koji Sasaki, Farhad Ravandi, Tapan M Kadia, Sa A Wang, Wei Wang, Sanam Loghavi, Naval G Daver, Courtney D DiNardo, Ghayas C Issa, Hussein A Abbas, Cedric Nasnas, Alex Bataller, Samuel Urrutia, Omer S Karrar, Sherry A Pierce, Hagop M Kantarjian, Nicholas J Short.
      The prognostic impact of measurable residual disease (MRD) in acute myeloid leukemia (AML) is unequivocal; however, the optimal timepoint for achieving undetectable MRD is unclear. We retrospectively studied patients with newly diagnosed (ND) AML who achieved remission with frontline intensive chemotherapy and had MRD assessed by flow cytometry after induction (TP1) and after cycles 2 or 3 (TP2). Cases were grouped into MRD Neg/Neg, Pos/Neg or Pos/Pos at TP1 and TP2, respectively. Of 1980 patients with ND AML, 277 met inclusion criteria and were included in this analysis. The median relapse-free survival (RFS) was 73 months, 22 months, and 5 months for the MRD Neg/Neg, Pos/Neg and Pos/Pos groups, respectively (p < 0.01). There was a significant difference between the Neg/Neg and Pos/Neg groups (p = 0.05), suggesting benefit to early MRD negativity. Median overall survival (OS) was 81 months, 40 months, and 9 months, respectively (p < 0.01), but the difference between Neg/Neg and Pos/Neg was not statistically significant (p = 0.19). Landmark analysis demonstrated the benefit of SCT, particularly in Neg/Neg intermediate risk AML (median RFS not reached versus 15 months, p < 0.01). On multivariable analysis, MRD Pos/Neg was independently associated with a worse RFS compared with Neg/Neg (hazard ratio 1.73 [95% CI, 1.09 - 2.75], p = 0.02) but not for OS (p = 0.15). In conclusion, undetectable flow MRD after induction is associated with better RFS compared with undetectable MRD achieved later during consolidation. SCT benefitted patients with intermediate risk AML, regardless of MRD kinetics.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013826
  2. Nat Methods. 2024 Dec 05.
    The dynamics of hematopoiesis over the human lifespan.
    Hojun Li, Parker Côté, Michael Kuoch, Jideofor Ezike, Katie Frenis, Anton Afanassiev, Laura Greenstreet, Mayuri Tanaka-Yano, Giuseppe Tarantino, Stephen Zhang, Jennifer Whangbo, Vincent L Butty, Enrico Moiso, Marcelo Falchetti, Kate Lu, Guinevere G Connelly, Vivian Morris, Dahai Wang, Antonia F Chen, Giada Bianchi, George Q Daley, Salil Garg, David Liu, Stella T Chou, Aviv Regev, Edroaldo Lummertz da Rocha, Geoffrey Schiebinger, R Grant Rowe.
      Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation and aging. Here we define the gene expression networks dictating age-specific differentiation of HSCs and the dynamics of fate decisions and lineage priming throughout life. We additionally identifiy and functionally validate a fetal-specific HSC state with robust engraftment and multilineage capacity. Furthermore, we observe that classification of acute myeloid leukemia against defined transcriptional age states demonstrates that utilization of early life transcriptional programs associates with poor prognosis. Overall, we provide a disease-relevant framework for heterochronic orientation of stem cell ontogeny along the real time axis of the human lifespan.
    DOI:  https://doi.org/10.1038/s41592-024-02495-0
  3. Blood. 2024 Dec 04. pii: blood.2024024063. [Epub ahead of print]
    Honing CAR T cells to tackle acute myeloid leukemia.
    Sascha Haubner, Marion Subklewe, Michel Sadelain.
      Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (r/r) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in r/r AML. Re-directing the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123 or CLEC12A has occasionally yielded morphological leukemia-free states (MLFS) but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations owe in large part to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multi-antigen targeting, logic-gating and emerging cell engineering solutions offer new possibilities to better direct T cell specificity and sensitivity towards AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.
    DOI:  https://doi.org/10.1182/blood.2024024063
  4. Ann Hematol. 2024 Nov 30.
    FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML.
    Toshihiro Matsukawa, Masahiro Onozawa, Takeshi Kondo, Minoru Kanaya, Daisuke Hidaka, Shuichi Ota, Akio Mori, Akio Shigematsu, Takuto Miyagishima, Yasutaka Kakinoki, Junichi Hashiguchi, Satoshi Yamamoto, Masayo Yamamoto, Kentaro Wakasa, Mutsumi Takahata, Toshimichi Ishihara, Yoshihito Haseyama, Akihito Fujimi, Tetsuya Igarashi, Takehiro Sarashina, Satoshi Iyama, Ryoji Kobayashi, Hajime Sakai, Katsuya Fujimoto, Junki Inamura, Yuji Kanisawa, Shinsuke Hirabayashi, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult de novo AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with FLT3-ITD AML in a real-world setting. We retrospectively analyzed 139 patients with FLT3-ITD-positive AML between 2012 and 2021. The median age was 63 years. In the propensity score-matched cohort, FLT3 inhibitors improved overall survival (OS) compared with patients treated without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p = 0.021). Patients who underwent HCT had superior outcomes to those without HCT (3-year OS: 45.3% vs. 2.2%, p < 0.0001). The combination of FLT3 inhibitors and HCT resulted in the highest OS and relapse-free survival (RFS) rates (3-year OS: 62.4%; 3-year RFS: 44.4%). Disease status before transplantation did not predict the prognosis, but use of FLT3 inhibitors increased survival in patients without complete remission before HCT. These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with FLT3-ITD-positive AML, particularly when combined with HCT. FLT3 inhibitors can improve the prognosis of AML with FLT3 mutations, especially in patients who undergo HCT.
    Keywords:   FLT3-ITD; Acute myeloid leukemia; FLT3 inhibitor; Hematopoietic cell transplantation
    DOI:  https://doi.org/10.1007/s00277-024-06125-9
  5. Haematologica. 2024 Dec 05.
    Evolution of myeloproliferative neoplasms from normal blood stem cells.
    Sahand Hormoz, Vijay G Sankaran, Ann Mullally.
      Over the course of the last decade, genomic studies in the context of normal human hematopoiesis have provided new insights into the early pathogenesis of myeloproliferative neoplasms (MPN). A preclinical phase of MPN, termed clonal hematopoiesis (CH) was identified and subsequent lineage tracing studies revealed a multi-decade long time interval from acquisition of an MPN phenotypic driver mutation in a hematopoietic stem cell (HSC) to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies (GWAS) and in some cases functional interrogation of the impact of the variant has uncovered new insights into HSC biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure HSC fitness have helped discern the biology underlying the tremendous clinical heterogeneity observed in MPN. Despite these advances, significant knowledge gaps remain particularly with respect to germline genetic contributors to both MPN pathogenesis and phenotypic diversity, as well as limitations in the ability to prospectively quantify rates of clonal expansion in individual MPN patients. Ultimately, we envisage a personalized approach to MPN care in the future, where an individualized genetic assessment can predict MPN trajectory and this information will be used to inform and guide therapy. MPN is particularly amenable to precision medicine strategies and our increased understanding of the evolution of MPN from normal blood stem cells provides a unique opportunity for early therapeutic intervention approaches and potentially MPN prevention strategies.
    DOI:  https://doi.org/10.3324/haematol.2023.283951
  6. Br J Haematol. 2024 Dec 02.
    Clinical perspectives on post-induction maintenance therapy in patients with acute myeloid leukaemia in remission who are ineligible for allogeneic haematopoietic stem cell transplantation.
    Kendra Sweet, Thomas Cluzeau.
      For patients with acute myeloid leukaemia (AML) who achieve complete remission (CR) after induction therapy, subsequent allogeneic haematopoietic stem cell transplantation (allo-HSCT) reduces the risk of relapse. However, not all patients are eligible, warranting effective alternative maintenance strategies. Oral azacitidine is the only non-targeted therapy approved by both the United States (US) Food and Drug Administration and the European Medicines Agency for the maintenance or continued treatment of allo-HSCT-ineligible patients with AML achieving CR or CR with incomplete haematological recovery following induction chemotherapy. Midostaurin and histamine dihydrochloride are approved in Europe as maintenance therapy for AML in remission, and quizartinib is approved in the United States and Europe for the treatment and maintenance of patients with newly diagnosed FLT3-ITD AML. Barriers to maintenance treatment include limited clinical trial data informing appropriate patient and treatment selection, patient preference, financial burden and paucity of real-world data. This article discusses current maintenance treatment guidelines for patients with AML in remission but not proceeding to allo-HSCT and reviews clinical trial data for agents approved for use in remission. Ongoing studies of interest and considerations for future efforts are also discussed.
    Keywords:  acute myeloid leukaemia; maintenance; measurable residual disease
    DOI:  https://doi.org/10.1111/bjh.19924
  7. Leukemia. 2024 Dec 04.
    Is there really an accelerated phase of chronic myeloid leukaemia at presentation?
    Sen Yang, Xiaoshuai Zhang, Robert Peter Gale, Xiaojun Huang, Qian Jiang.
      Whether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukaemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy is controversial. We studied 2122 consecutive subjects in chronic phase (CP, n = 1837) or AP (n = 285) at diagnosis classified according to the 2020 European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects classified as ELTS intermediate-risk. Those with increased blasts only had worse TFS but similar survival compared with CP subjects classified as ELTS high-risk. AP subjects with decreased platelets only had similar TFS but worse survival compared with subjects classified as ELTS high-risk. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. However, worse TFS at 3-month and survival at 6- or 12-month were only in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria for AP replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases at diagnosis: CP and acute or blast phases.
    DOI:  https://doi.org/10.1038/s41375-024-02486-2
  8. Blood Adv. 2024 Dec 05. pii: bloodadvances.2024014490. [Epub ahead of print]
    Advantages of a genomic DNA-based NGS assay for detection of mutant NPM1 measurable residual disease in AML.
    Christian M Vonk, Tim Grob, Melissa Rijken, François G Kavelaars, Jolinda Konijnenburg, Gert J Ossenkoppele, Markus G Manz, Yngvar Floisand, Bob Löwenberg, Peter J M Valk.
      Mutations in the Nucleophosmin-1 (NPM1) gene are among the most common molecular aberrations in acute myeloid leukemia (AML). Various studies have established mutant NPM1 (mNPM1) as a faithful molecular measurable residual disease (MRD) marker with prognostic significance. Assessment of prognostic mNPM1 is included in the European LeukemiaNet (ELN) recommendations on MRD detection in AML. Due to recent advancements of promising drugs targeting mNPM1 AML, monitoring of mNPM1 MRD has gained interest, and is generally done by reverse transcriptase quantitative PCR (RT-qPCR). However, these RT-qPCR assays use cDNA as input, are based on gene expression levels of mNPM1, and are generally limited to specific mNPM1 gene variants. The main advantages of next-generation sequencing (NGS) using genomic DNA as input are stability, independence of gene expression levels, and the ability to detect any NPM1 variant in a single assay. Here we comprehensively investigated the applicability of NGS on DNA to detect mNPM1 MRD in a cohort of 119 (cDNA) and 310 (DNA) mNPM1 AML patients in complete remission after two cycles of induction chemotherapy. We demonstrate high correlations in levels and prognostic value between RT-qPCR/cDNA and NGS/DNA approaches, postulating NGS/DNA as an attractive alternative to RT-qPCR. We report that the 2% mNPM1/ABL1 threshold by RT-qPCR/cDNA corresponds to a NGS/DNA variant allele frequency (VAF) of 0.01%. The NGS/DNA threshold of >0.01% after two cycles of induction chemotherapy identifies significantly more AML patients with an increased relapse risk than current RT-qPCR/cDNA assays. The prognostic significance of mNPM1 MRD appears greatest in FLT3-ITD AML patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014490
  9. Blood Adv. 2024 Dec 04. pii: bloodadvances.2024014467. [Epub ahead of print]
    Single cell multiomics reveal divergent effects of DNMT3A and TET2 mutant clonal hematopoiesis in inflammatory response.
    Wazim Mohammed Ismail, Jenna Fernandez, Moritz Binder, Terra L Lasho, Minsuk Kim, Susan Geyer, Amelia Mazzone, Christy M Finke, Abhishek A Mangaonkar, Jeong-Heon Lee, Liguo Wang, Kwan Hyun Kim, Vernadette A Simon, Fariborz Rakhshan Rohakthar, Amik Munankarmy, Seul Kee Byeon, Susan M Schwager, Jonathan J Harington, Melissa R Snyder, Keith D Robertson, Akhilesh Pandey, Eric D Wieben, Nicholas Chia, Alexandre Gaspar-Maia, Mrinal M Patnaik.
      DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematological neoplasms. While individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome-ARDS) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant CH on COVID-19-related ARDS and mortality. Using single cell (sc-) proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of IL32, a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19 related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014467
  10. Haematologica. 2024 Dec 05.
    Does size matter? Center-specific characteristics and survival after allogeneic hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry for Stem Cell Transplantation and Cell Therapy.
    Wolfgang Bethge, Sarah Flossdorf, Franziska Hanke, Christoph Schmid, Mark Ringhoffer, Stefan Klein, Bernd Hertenstein, Johannes Schetelig, Matthias Stelljes, Thomas Schroeder, Igor Wolfgang Blau, Francis Ayuk, Matthias Eder, Robert Zeiser, Katharina Fleischhauer, Nicolaus Kröger, Peter Dreger.
      We investigated the effect of center-specific variables on overall survival (OS) after allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML). Eligible were adult patients reported to DRST registry receiving first alloHCT for AML from a related or matched (>= 9/10 HLA-match) unrelated donor 2015-2021. Primary endpoint was OS at 12 months from alloHCT. Univariable and multivariable analyses after best subset selection was performed. Of 5328 patients, 83% received alloHCT in a high-volume center (≥40 alloHCT/year); 90% in a university hospital; 90% in a center performing alloHCT for ≥10 years; and 73% in a Joint Accreditation Committee IHCT-Europe and EBMT (JACIE) accredited center. 52% of the patients were in CR1, and ELN risk was adverse in 37% and intermediate in 42%. On multivariable analysis, center-specific factors predicting adverse 12-month OS were program duration.
    DOI:  https://doi.org/10.3324/haematol.2024.286385
  11. J Exp Med. 2025 Jan 06. pii: e20230931. [Epub ahead of print]222(1):
    Genetic and environmental risks for clonal hematopoiesis and cancer.
    Stephanie Franco, Lucy A Godley.
      Somatic variants accumulate in all organs with age, with a positive selection of clonal populations that provide a fitness advantage during times of heightened cellular stress leading to clonal expansion. Easily measured within the hematopoietic compartment, clonal hematopoiesis (CH) is now recognized as a common process in which hematopoietic clones with somatic variants associated with hematopoietic neoplasms exist within the blood or bone marrow of individuals without evidence of malignancy. Most cases of CH involve a limited number of genes, most commonly DNMT3A, TET2, and ASXL1. CH confers risk for solid and hematopoietic malignancies as well as cardiovascular and numerous inflammatory diseases and offers opportunities for cancer prevention. Here, we explore the genetic and environmental factors that predispose individuals to CH with unique variant signatures and discuss how CH drives cancer progression with the goals of improving individual cancer risk stratification, identifying key intervention opportunities, and understanding how CH impacts therapeutic strategies and outcomes.
    DOI:  https://doi.org/10.1084/jem.20230931
  12. Blood Adv. 2024 Dec 03. pii: bloodadvances.2024013446. [Epub ahead of print]
    TIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A.
    Yang Wang, Yan Xiu, Qianze Dong, Jinming Zhao, Kelao Neumbo, Masaru Miyagi, Nicholas Borcherding, Lin Fu, Havana Ray De Celis, Nicolas Giuseppe Pintozzi, Daniel T Starczynowski, Chen Zhao.
      TRAF-interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-kB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3-driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15 (USP15)-mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3-induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene Set Enrichment Analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation (OXPHOS). By comparing genes upregulated in TIFAB-overexpressing LSPCs with those downregulated upon Tifab deletion, we identify hepatocyte nuclear factor 4alpha (Hnf4a) as a key TIFAB target, regulated through the inhibition of NF-kB component RelB, which suppresses Hnf4a in leukemia cells. HNF4A, a nuclear receptor involved in organ development, metabolism, and tumorigenesis, rescues the metabolic defects caused by Tifab deletion and enhances leukemia cell engraftment. Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3-induced AML and uncover a novel regulator in leukemia biology.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013446
  13. Cancer. 2024 Dec 01.
    Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety.
    Lucia Masarova, John Mascarenhas, Raajit Rampal, Wilson Hu, Robert A Livingston, Naveen Pemmaraju.
      The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast-phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC-PV, RESPONSE, RESPONSE-2, RELIEF, and Ruxo-BEAT), large real-world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well-characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard-of-care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a preferred treatment as monotherapy and as a potential backbone of future combination regimens.
    Keywords:  JAK inhibitor; JAK2V617F; MAJIC‐PV; RELIEF; RESPONSE; REVEAL; Ruxo‐BEAT; polycythemia vera; ruxolitinib
    DOI:  https://doi.org/10.1002/cncr.35661
  14. Haematologica. 2024 Dec 05.
    Pathogenesis and management of high molecular risk myeloproliferative neoplasms.
    Victoria Y Ling, Florian H Heidel, Megan J Bywater.
      Classical myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterised by driver mutations that affect the constitutive activation of JAK-signalling. Additional mutations to an MPN-driver occur in a large number of patients and have been shown be associated with disease presentation and progression. In this review, we will outline the current hypotheses regarding how clonal evolution in MPN is thought to occur and the functional mechanisms as to how concomitant somatic mutations (i.e. mutations in genes other than the 'driver' genes) contribute to disease progression. We will discuss the definitions of high molecular risk MPN, provide an overview as to how concomitant mutations influence the clinical management of MPN and suggest how this rapidly developing genetic risk stratification can be utilised to improve clinical outcomes.
    DOI:  https://doi.org/10.3324/haematol.2023.283987
  15. Leukemia. 2024 Dec 04.
    HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia.
    Saioa Arza-Apalategi, Branco M H Heuts, Saskia M Bergevoet, Roos Meering, Daan Gilissen, Pascal W T C Jansen, Anja Krippner-Heidenreich, Peter J M Valk, Michiel Vermeulen, Olaf Heidenreich, Torsten Haferlach, Joop H Jansen, Joost H A Martens, Bert A van der Reijden.
      KMT2A::MLLT3 acute myelomonocytic leukemia (AML) comes in two clinically and biologically different subtypes. One is characterized by inferior outcome, older age, and MECOM oncogene expression. The other is mainly observed in children and young adults, associates with better clinical outcome, but lacks MECOM. To identify cell fate determining transcription factors downstream of KMT2A::MLLT3, we applied a bioinformatic algorithm that integrates gene and enhancer expression from primary MECOM-positive and -negative KMT2A::MLLT3 AML samples. This identified MECOM to be most influential in the MECOM-positive group, while neuronal transcription factor HMX3 was most influential in the MECOM-negative group. In large AML cohorts, HMX3 expression associated with a unique gene expression profile, younger age (p < 0.002) and KMT2A-rearranged and KAT6A-CREBBP leukemia (p < 0.00001). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. RNA-sequencing analyses following forced HMX3 expression in healthy CD34+ cells and its silencing in KMT2A::MLT3 cells showed that HMX3 drives cancer-associated E2F and MYC gene programs (p < 0.001). HMX3 expression in healthy CD34+ cells blocked monocytic but not granulocytic colony formation. Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.
    DOI:  https://doi.org/10.1038/s41375-024-02485-3
  16. Blood Adv. 2024 Dec 05. pii: bloodadvances.2024014014. [Epub ahead of print]
    Trial eligibility, treatment patterns and outcome for venetoclax-based therapy in AML: a prospective cohort study.
    Ofir Wolach, Itai Levi, Boaz Nachmias, Sigal Tavor, Irina Amitai, Yishai Ofran, Chezi Ganzel, Tsila Zuckerman, Doaa Okasha, Ilana Hellmann, Tamar Tadmor, Najib Dally, Jonathan Canaani, Galia Stemer, Moshe Grunspan, Adi Jacob Berger, Neta Frankel, Jenia Berelovich, Alexandra Bleterman, Moran Barak, Raanan Cohen, Yakir Moshe.
      Venetoclax (Ven) plus hypomethylating agents are considered standard-of-care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, since patterns of patient selection, treatment-exposure and post-remission management may vary. This prospective observational multi-center study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range 0.1-43), median overall-survival (mOS) was 11.7 months (95% Confidence Interval [CI] 9.9,15.4). Composite complete remission (CRc) was achieved in 65.2% (CR 44.4%; CRi 20.8%). Of responding patients, 21.1% underwent stem-cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (p=0.027). AML ontogeny (p=0.024), reduced kidney function (p=0.001), Charlson co-morbidity index (CCI; p=0.0017), ELN-risk (p=0.01) and body-mass index (p=0.0298) were significantly associated with OS. Multivariant Cox-regression analysis confirmed independent association of OS with AML ontogeny (p=0.012), CCI (p=0.033) and ELN-risk (p=0.019). Patients enrolled in the latter half of the study period demonstrated improved OS compared to those enrolled earlier (p=0.026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. (clinicaltrials.gov: #NCT03987958).
    DOI:  https://doi.org/10.1182/bloodadvances.2024014014
  17. Ann Hematol. 2024 Dec 04.
    Survival impact of hypoxia-inducible factor-1 alpha (HIF-1α) in Nucleophosmin1 mutated acute myeloid leukemia.
    Chantiya Chanswangphuwana, Narittee Sukswai, Nichthida Tangnuntachai, Ponlapat Rojnuckarin.
      Nucleophosmin1 (NPM1) mutated acute myeloid leukemia (AML) without FLT3-ITD mutation is classified as a favorable risk AML which responds well to cytarabine therapy. Hypoxia-inducible factor-1 alpha (HIF-1α) promotes leukemic cell survival and maintains leukemic stem cell quiescence possibly contributing to cytarabine resistance. This study evaluated HIF-1α expression using immunohistochemistry in bone marrow of 29 newly diagnosed NPM1+FLT3-ITD- normal karyotype AML patients and analyzed its correlation with survival. All patients achieved complete remission after standard induction chemotherapy and proceeded to cytarabine consolidations. Positive HIF-1α staining with golgi body pattern and strong cytoplasmic HIF-1α expression was identified in 34.5% and 58.6% of patients, respectively. The expression of golgi body or strong cytoplasmic HIF-1α expression was related to increased relapse (p = 0.048) with significantly inferior relapse-free survival (RFS, p = 0.042). Using multivariate analysis, extramedullary disease at diagnosis was revealed as an independent prognostic factor for adverse RFS (hazard ratio [HR] 3.82; 95% confidence interval [CI] 1.26-11.55, p = 0.018), while golgi body or strong cytoplasmic HIF-1α expression showed a trend toward poor RFS (HR 3.56; 95% CI 1.00-12.69, p = 0.050). In summary, high HIF-1α expression is potentially a baseline prognostic biomarker for poor RFS and cytarabine resistance in NPM1+FLT3-ITD- AML. Further studies with the large number of patients are warranted.
    Keywords:   NPM1-mutated AML; Nucleophosmin1 ; Acute myeloid leukemia; Cytarabine; Hypoxia-inducible factor-1 alpha
    DOI:  https://doi.org/10.1007/s00277-024-06124-w
  18. Hemasphere. 2024 Dec;8(12): e70001
    Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.
    Daniel Pölöske, Helena Sorger, Anna Schönbichler, Elvin D de Araujo, Heidi A Neubauer, Anna Orlova, Sanna H Timonen, Diaaeldin I Abdallah, Aleksandr Ianevski, Heikki Kuusanmäki, Marta Surbek, Elisabeth Heyes, Thomas Eder, Christina Wagner, Tobias Suske, Martin L Metzelder, Michael Bergmann, Maik Dahlhoff, Florian Grebien, Roman Fleck, Christine Pirker, Walter Berger, Emir Hadzijusufovic, Wolfgang R Sperr, Lukas Kenner, Peter Valent, Tero Aittokallio, Marco Herling, Satu Mustjoki, Patrick T Gunning, Richard Moriggl.
      The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.
    DOI:  https://doi.org/10.1002/hem3.70001
  19. Cell Death Dis. 2024 Nov 30. 15(11): 869
    High iASPP (PPP1R13L) expression is an independent predictor of adverse clinical outcome in acute myeloid leukemia (AML).
    Mihada Bajrami Saipi, Alessia Ruiba, Marcus Matthias Schittenhelm, Gunnar Blumenstock, Balázs Győrffy, Serena Fazio, Marlon Hafner, Anna-Lena Ahrens, Lara Aldinger, Vanessa Aellig, François G Kavelaars, César Nombela-Arrieta, Falko Fend, Peter J M Valk, Driessen Christoph, Kerstin Maria Kampa-Schittenhelm.
      Apoptosis-stimulating proteins of p53 (ASPPs) are a family of proteins that modulate key tumor suppressor pathways via direct interaction with p53. Deregulation of these proteins promotes cancer development and impairs sensitivity to systemic (chemo)therapy and radiation. In this study, we describe that the inhibitor of ASPP (iASPP) is frequently highly expressed in acute myeloid leukemia (AML) and that overexpression correlates with a poor clinical outcome. Four independent patient cohorts comprising about 1500 patient samples were analysed and consistently confirm an association of high iASPP expression with unfavourable clinical characteristics and shorter survival. Notably, the predictive role of iASPP is independent of, and adds information to, the European LeukemiaNET (ELN) risk classification. iASPP-interference cell models were developed to investigate the underlying functional aspects of iASPP in AML biology. Attenuation of iASPP expression resulted in reduced proliferation rates of leukemic blasts and rendered cells more susceptible towards induction of apoptosis in response to cytotoxic therapy. In line, independent NSG xenograft mouse experiments demonstrate that attenuation of iASPP results in a significant delay of disease onset and tumor burden and this translates to longer overall survival of mice. In conclusion, deregulation of iASPP has direct functional consequences in AML. Determination of iASPP expression levels provides valuable additional information as a predictive marker in AML and may guide treatment decisions.
    DOI:  https://doi.org/10.1038/s41419-024-07190-8
  20. Haematologica. 2024 Dec 05.
    Treatment of high risk myelodysplastic syndrome.
    Nicolaus Kröger.
      The myelodysplastic syndrome (MDS) is considered to be a heterogeneous myeloid malignancy with a common origin in the hematopoietic stem cell compartment, generally divided into lower and higher risk. While treatment goal for lower risk MDS (LR-MDS) is to decrease transfusion burden and transformation into acute leukemia major aim for high risk MDS is to prolong survival and ultimately cure. While novel agents such as luspatercept or imetelstat have recently been approved as new treatment options for LR-MDS, hypomethylating agents (HMA) remain currently the only approved non-transplant option for HR-MDS and is the standard of care for non-transplant-eligible patients. Combinations with other drugs as first-line treatment has to date not proven more efficacious than monotherapy in HR-MDS, and outcome after HMA failure is poor. The only potential cure and standard of care for eligible patients is allogeneic stem cell transplantation (HSCT) and even if the number of transplanted - especially older - MDS patients increased over time due to a better management and donor availability the majority of MDS patients will not be eligible for this curative approach. Current challenges encompass to decrease the relapse risk, the main cause of HSCT failure. This review will summarize current knowledge of options of transplant- and non-transplant treatment approaches for these patients and demonstrate the unmet clinical need for more effective therapies.
    DOI:  https://doi.org/10.3324/haematol.2023.284946
  21. Nature. 2024 Dec 04.
    Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
    Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.
      Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
    DOI:  https://doi.org/10.1038/s41586-024-08285-0
  22. Blood Res. 2024 Dec 02. 59(1): 39
    How to improve AML outcomes?
    Taner Tan, Sinem Civriz Bozdag.
      Understanding the intricacies of the pathophysiology and genomic landscape has enhanced the long-term outcomes for patients with acute myeloid leukemia (AML). The identification of novel molecular targets has introduced new therapeutic strategies that attempt to surpass the dominance of the "7 + 3 regimen" established in the 1970s. In 2022, the World Health Organization and International Consensus Classification revised their definitions and approaches to AML, reflecting the current and evolving changes at the molecular level. The guidelines are now grounded in a definition of the disease that emphasizes genetic characteristics. Today, we recognize AML as a genetically diverse disease; a retrospective study identified 5234 driver mutations across 76 genes or genomic regions, with two or more drivers observed in 86% of patients (Papaemmanuil et al., N Engl J Med 374:2209-21, 2016).
    Keywords:  AML; Mutations; Outcome; Relapsed; Targeted; Treatment
    DOI:  https://doi.org/10.1007/s44313-024-00041-7
  23. Cell Rep Med. 2024 Nov 26. pii: S2666-3791(24)00606-2. [Epub ahead of print] 101835
    Age-related clonal hematopoiesis and HIV infection are associated with geriatric outcomes: The ARCHIVE study.
    ARCHIVE Study Group
      While HIV infection and clonal hematopoiesis (CH) have been linked with inflammatory dysregulation and an increased risk of aging-related comorbidities, their relationship with clinical geriatric syndromes has not been well defined. In the Age-related Clonal Haematopoiesis in an HIV Evaluation Cohort (ARCHIVE) study (NCT04641013), we measure associations between HIV and CH and geriatric syndromes. Of 345 participants (176 with HIV and 169 without HIV), 23% had at least one mutation associated with CH: 27% with HIV and 18% without HIV (p = 0.048). In adjusted analyses, HIV infection is independently associated with increased phenotypic age acceleration (coefficient 1.73, 95% confidence interval [CI] 0.3, 3.16) and CH is independently associated with being frail (vs. pre-frail/robust; odds ratio 2.38, 95% CI 1.01, 5.67) and with having reduced quality of life (coefficient -2.18, 95% CI -3.92, -0.44). Our findings suggest that HIV is associated with increased biological age and that CH may be used as a biomarker for adverse geriatric outcomes.
    Keywords:  HIV; aging-related comorbidities; clonal hematopoiesis; frailty; geriatric syndromes; multimorbidity; phenotypic age acceleration; quality of life
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101835
  24. Blood Cancer Discov. 2024 Dec 03.
    CD33-CD123 IF-THEN gating reduces toxicity while enhancing the specificity and memory phenotype of AML-targeting CAR-T cells.
    Samy Jambon, Jianping Sun, Shawn Barman, Sakunthala Muthugounder, Xue Rachel Bito, Armita Shadfar, Alexandra E Kovach, Brent L Wood, Varsha Thoppey Manoharan, A Sorana Morrissy, Deepa Bhojwani, Alan S Wayne, Michael A Pulsipher, Yong-Mi Kim, Shahab Asgharzadeh, Chintan Parekh, Babak Moghimi.
      CAR T-cell therapy has remarkably succeeded in treating lymphoblastic leukemia. However, its success in AML remains elusive due to the risk of on-target off-tumor toxicity to hematopoietic stem and progenitor cells (HSPC) and insufficient T-cell persistence and longevity. Using a SynNotch circuit, we generated a high-precision "IF-THEN" gated logical circuit against the combination of CD33 and CD123 AML antigens and demonstrated anti-tumor efficacy against AML cell lines and patient-derived xenografts. Unlike constitutively expressed CD123 CAR-T cells, those expressed through the CD33 SynNotch circuit could preserve HSPCs and lower the risk of on-target off-tumor hematopoietic toxicity. These gated CAR-T cells exhibited lower expression of exhaustion markers (PD1, Tim3, LAG3, and CD39), higher frequency of memory T cells (CD62L+CD45RA+), and enhanced expansion. While targeting AML, the moderated circuit CAR signal also helped to mitigate cytokine release syndrome, potentially addressing one of the ongoing challenges in CAR-T immunotherapy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0258
  25. Cancer Res Commun. 2024 Dec 05.
    Clonal hematopoiesis of indeterminate potential (CHIP) and its association with treatment outcomes and adverse events in patients with solid tumours.
    Tharani Krishnan, Joao Paulo Solar Vasconcelos, Emma Titmuss, Robert J Vanner, David F Schaeffer, Aly Karsan, Howard Lim, Cheryl Ho, Sharlene Gill, Stephen Yip, Stephen K Chia, Hagen F Kennecke, Derek J Jonker, Eric X Chen, Daniel J Renouf, Chris J O'Callaghan, Jonathan M Loree.
      Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of hematopoietic stem cells from somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumours and explored its association with treatment outcomes and adverse events. We reviewed cfDNA results from a local prospective solid tumour cohort (PREDiCT-l) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care in metastatic colorectal cancer) and CCTG PA.7 (gemcitabine and nab-paclitaxel +/- D+T in metastatic pancreatic adenocarcinoma). CHIP+ was defined as any mutation in DNMT3A, TET2 or ASXL1 with a variant allele frequency (VAF) ≥2% Presumed germline variants (VAF>40%) were removed. The first line of treatment after cfDNA was reviewed for grade 3 and dose-limiting toxicities. The prevalence of CHIP in the 465 included patients was 10-30% and it was more common as age increased (p=0.003). DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy showed an improved progression-free survival (PFS) versus CHIP- (HR 0.55 [0.28-1.07], p=0.079, p-interaction=0.098 [multivariable]). However, patients with CHIP treated with chemotherapy in PREDiCT-l showed a trend towards worse PFS (HR 1.82 [0.98-3.38], p=0.059). There was no difference in adverse event rates between CHIP+/- groups for those treated with chemotherapy or immunotherapy. CHIP is common in patients with solid tumours. Although not appearing to impact rates of adverse events, CHIP may impact outcomes from immunotherapy or chemotherapy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0522
  26. Nature. 2024 Dec 04.
    Fetal hepatocytes protect the HSPC genome via fetuin-A.
    Xiao-Lin Guo, Yi-Ding Wang, Yan-Jun Liu, Lei Chu, Hua Zhu, Ye Hu, Ren-Yan Wu, Hong-Yu Xie, Juan Yu, Shui-Ping Li, Zhao-Yang Xiong, Ruo-Yan Li, Fang Ke, Lei Chen, Guo-Qiang Chen, Liang Chen, Fan Bai, Tariq Enver, Guo-Hong Li, Huai-Fang Li, Deng-Li Hong.
      The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development1-3. Although numerous cell-intrinsic mechanisms have been revealed4-7, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua-knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.
    DOI:  https://doi.org/10.1038/s41586-024-08307-x
  27. J Clin Oncol. 2024 Dec 02. JCO2401715
    Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.
    Claudia Tregnago, Maddalena Benetton, Rhonda E Ries, Jack H Peplinski, Todd A Alonzo, Derek Stirewalt, Megan Othus, Nicolas Duployez, Edwin Sonneveld, Jonas Abrahamsson, Linda Fogelstrand, Nils von Neuhoff, Henrik Hasle, Dirk Reinhardt, Soheil Meshinchi, Franco Locatelli, Martina Pigazzi.
       PURPOSE: Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.
    MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied.
    RESULTS: Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.
    CONCLUSION: The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.
    DOI:  https://doi.org/10.1200/JCO-24-01715
  28. Blood Adv. 2024 Dec 04. pii: bloodadvances.2024014590. [Epub ahead of print]
    Venetoclax-Proteasome inhibitor-Dexamethasone for unfit patients with Blastic Plasmacytoid Dendritic Cell Neoplasm.
    Sabine Khalife-Hachem, Arnaud Pages, Elie Akoury, Sarah Bonnet, Rudy Birsen, Clemence Busquet, Adrien Contejean, Alina Danu, Stéphane De Botton, Marie De Charette, Pierre-Yves Dumas, Arnaud Jaccard, Anne Marfaing-Koka, Christophe Willekens, Eric Deconinck, David Ghez.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024014590
  29. Nat Rev Drug Discov. 2024 Dec 03.
    FDA approves first menin inhibitor, for acute leukaemia.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-024-00198-x
  30. JCO Glob Oncol. 2024 Nov;10 e2400316
    Global Disparities in the Characteristics and Outcomes of Leukemia Clinical Trials: A Cross-Sectional Study of the ClinicalTrials.gov Database.
    Abdulrahman Alhajahjeh, Lara K Rotter, Jessica M Stempel, Alyssa A Grimshaw, Jan Philipp Bewersdorf, Ondrej Blaha, Tariq Kewan, Nikolai A Podoltsev, Rory M Shallis, Lourdes Mendez, Maximilian Stahl, Amer M Zeidan.
       PURPOSE: Most clinical trials are conducted exclusively in high-income countries (HICs), with only a small fraction involving centers from low-middle income countries (LMICs). However, studies evaluating the global distribution of clinical trials in leukemia are limited. Therefore, we sought to assess the present state of leukemia clinical trials that involve centers from LMICs and to compare those with trials conducted exclusively in HICs.
    MATERIALS AND METHODS: We searched ClinicalTrials.gov to identify leukemia trials initiated between 2000 and 2020. In this cross-sectional study, the search strategy was developed by a medical librarian using controlled vocabulary and free-text terms. Data abstraction was independently executed by two reviewers. Trials were defined to be LMIC trials if they included centers from LMICs according to the World Bank Atlas country's income level classification for 2022-2023. Conversely, if a trial included centers from HICs only, the study was classified as a HIC trial.
    RESULTS: Of 3,345 leukemia-related clinical trials identified, only 160 (4.8%) included centers from LMICs. Compared with HIC trials, LMIC trials had lower termination rates (12.5% v 27.5%; P < .001) and were more likely randomized (52.5% v 18.2%; P < .001), larger (sample sizes >50 patients: 69.0% v 33.6%; P < .001), multicenter (81.9% v 47.9%; P < .001), and later phase (phase III: 36.2% v 8.98%; P < .001; phase IV: 6.25% v 2.17%; P < .001). There was an increase in the proportion of randomized and diseased-focused clinical trials within the trials that involved LMIC centers between 2000-2005 and 2010-2015 (57.1% v 47.1% and 85.7% v 52.9%; P = .013 and 0.014, respectively).
    CONCLUSION: We found a marked underrepresentation of LMICs in leukemia clinical trials reflecting limited access to novel leukemia therapies in LMICs.
    DOI:  https://doi.org/10.1200/GO-24-00316
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