bims-tremyl 2025-03-09 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–03–09
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Myeloid neoplasms with PHF6 mutations: context-dependent genomic and prognostic characterization in 176 informative cases.
Prevalence of cytopenia(s) and somatic variants in patients with DDX41 mutant germline predisposition syndrome.
Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage.
The IKZF1 N159S mutation is associated with poor outcome and a distinct molecular profile in adult patients with AML.
Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes.
Clonal dynamics and somatic evolution of haematopoiesis in mouse.
Metabolic alterations in HSCs during aging and leukemogenesis.
Safety Run-In and Part 1 of GIMEMA AML1718: Venetoclax Combined with FLAI as Induction Treatment in Non-Low-Risk AML.
DNMT3A regulates murine megakaryocyte-biased hematopoietic stem cell fate decisions.
Transplant Outcomes Using Older Matched Sibling Donors Compared to Young Alternative Donors: A CIBMTR Analysis.
Impact of baseline genetic profile and treatment on outcome and hematological toxicity in CEBPA-mutated AML.
BCL11A-deficient human erythropoiesis is impaired in vitro and after xenotransplantation into mice.
Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
Hematopoietic stem cells undergo bidirectional fate transitions in vivo.
CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis.
TP53-Mutated Acute Myeloid Leukemia: Review of Treatment and Challenges.
WTAP-mediated m6A methylation of PHF19 facilitates cell cycle progression by remodeling the accessible chromatin landscape in t(8;21) AML.
Real world efficacy of luspatercept in patients with lower-risk myelodysplastic syndromes/neoplasms (MDS); a single center study in a heavily pretreated cohort.
Restoring mitochondrial function promotes hematopoietic reconstitution from cord blood following cryopreservation-related functional decline.
SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer.
A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.
Tackling Cancer through Global Team Science.
Management of children and adolescents with chronic myeloid leukemia in chronic phase: International pediatric chronic myeloid leukemia expert panel recommendations.

Blood Cancer J. 2025 Mar 01. 15(1): 28

Myeloid neoplasms with PHF6 mutations: context-dependent genomic and prognostic characterization in 176 informative cases.

Saubia Fathima, Ali Alsugair, Rong He, Abhishek A Mangaonkar, Kebede H Begna, Animesh Pardanani, Cinthya J Zepeda Mendoza, Kaaren K Reichard, Naseema Gangat, Ayalew Tefferi.

Recent reports suggest a favorable prognosis for PHF6 mutation (PHF6MUT) in chronic myelomonocytic leukemia (CMML) and unfavorable in acute myeloid leukemia (AML). We accessed 176 consecutive patients with a spectrum of myeloid neoplasms with PHF6MUT, including AML (N = 67), CMML (N = 49), myelodysplastic syndromes (MDS; N = 36), myeloproliferative neoplasms (MPN; N = 16), and MDS/MPN (N = 8). PHF6 mutations were classified as nonsense (43%) or frameshift (30%) with the PHD2 domain being the most frequently (64%) affected region. Median follow-up was 25 months with 110 (63%) deaths and 44 allogenic transplants. Our top-line observations include (a) a distinctly superior overall survival (OS; 81 vs. 18 months; p < 0.01) and blast transformation-free survival (BTFS; "not reached" vs. 44 months; p < 0.01) in patients with CMML vs. those with other myeloid neoplasms, (ii) a higher than expected frequency of isolated loss of Y chromosome, in the setting of CMML (16% vs. expected 6%) and MDS (8% vs expected 2.5%), (iii) a significant association, in MDS, between PHF6MUT variant allele fraction (VAF) > 20% and inferior OS (HR 3.0, 95% CI 1.1-8.1, multivariate p = 0.02) as well as female gender and inferior BTFS (HR 26.8, 95% CI 1.9-368.3, multivariate p = 0.01), (iv) a relatively favorable median post-transplant survival of 46 months. Multivariable analysis also identified high-risk karyotype (HR 5.1, 95% CI 1.2-20.9, p = 0.02), and hemoglobin <10 g/dL (HR 2.7, 95% CI 1.0-7.2, p = 0.04), as independent predictors of inferior OS in patients with MDS. The current study provides disease-specific information on genotype and prognosis of PHF6-mutated myeloid neoplasms.

DOI: https://doi.org/10.1038/s41408-025-01231-x
Br J Haematol. 2025 Mar 04.

Prevalence of cytopenia(s) and somatic variants in patients with DDX41 mutant germline predisposition syndrome.

Yael Kusne, Talha Badar, Terra Lasho, Ludovica Marando, Abhishek A Mangaonkar, Christy Finke, James M Foran, Aref Al-Kali, Jeanne Palmer, Cecilia Arana Yi, Hassan B Alkhateeb, Naseema Gangat, David Viswanatha, Mark R Litzow, Timothy Chlon, Alejandro Ferrer, Mrinal M Patnaik.

  Germline variants in DDX41 (DDX41MT-germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41MT-GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2-93.4). Ninety-two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41MT-GPS cohort.

Keywords:  AML; CCUS; CHIP; MDS; germline DDX41; germline predisposition syndromes

DOI:  https://doi.org/10.1111/bjh.20018
Exp Hematol Oncol. 2025 Mar 05. 14(1): 31

Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage.

Aurora Bernal, Vincent Cuminetti, Marc Serulla, Adrian Florit, Joanna Konieczny, Golnaz Golnarnik, Yimeng Chen, Marc Ferré, Samuel Geiseler, Anders Vik, Randi Olsen, Lorena Arranz.

  The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9+ acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3-6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin+ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRASG12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRASG12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRASG12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.

Keywords:  Hematological cancers; Peripheral nervous system; Stem cell niche; Sympathetic fibres; Transmission electron microscopy

DOI:  https://doi.org/10.1186/s40164-025-00614-x
Br J Haematol. 2025 Mar 05.

The IKZF1 N159S mutation is associated with poor outcome and a distinct molecular profile in adult patients with AML.

Study Alliance Leukemia (SAL)

  IKZF1 mutations are recurrent alterations in acute myeloid leukaemia (AML), and hotspot point mutation, N159S, has recently been associated with unique gene expression and adverse risk. To better understand the molecular and clinical associations of IKZF1 N159S-mutated AML, we performed a pooled analysis of 4136 AML patients. IKZF1 N159 mutations were found in 39 patients (0.94%) in a dominant clonal constellation, indicating early genetic events. N159S mutations were associated with aberrant karyotype, significantly higher rates of myelodysplasia-related gene mutations, ELN2022 adverse risk and a particularly poor outcome, supporting the classification of IKZF1 N159S-mutated AML as a rare molecular subtype with adverse prognosis.

Keywords:   IKZF1 ; N159S mutation; acute myeloid Leukaemia (AML); clinical outcome; molecular associations

DOI:  https://doi.org/10.1111/bjh.20027
Cell Rep Med. 2025 Feb 28. pii: S2666-3791(25)00062-X. [Epub ahead of print] 101989

Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes.

Marco M Buttigieg, Caitlyn Vlasschaert, Alexander G Bick, Robert J Vanner, Michael J Rauh.

  Clonal hematopoiesis (CH)-the expansion of somatically mutated hematopoietic cells-is common in solid cancers. CH is associated with systemic inflammation, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naive patient samples from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort. CH is present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. Across cancers, the presence of CH-Tum is associated with worse survival outcomes. Molecular analyses reveal an association between CH-Tum and an immune-rich, inflammatory TME that is notably distinct from age-related gene expression changes. These effects are most prominent in glioblastoma, where CH correlates with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.

Keywords:  CPTAC; TCGA; cancer; clonal hematopoiesis; clonal hematopoiesis of indeterminate potential; glioblastoma; immunity; inflammation; precision oncology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.101989
Nature. 2025 Mar 05.

Clonal dynamics and somatic evolution of haematopoiesis in mouse.

Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia.

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

DOI: https://doi.org/10.1038/s41586-025-08625-8
Physiology (Bethesda). 2025 Feb 28.

Metabolic alterations in HSCs during aging and leukemogenesis.

Yi-Hsuan Chiang, Stephan Emmrich, Nicola Vannini.

  Aging is a multifaceted process associated with a functional decline in cellular function over time, affecting all lifeforms. During the aging process, metabolism, a fundamental hallmark of life (1), is profoundly altered. In the context of hematopoiesis, the proper function of hematopoietic stem cells - at the apex of the blood system - is tightly linked to their energy metabolism, which in turn shapes hematopoietic output. Here, we review the latest developments in our understanding of the metabolic states and changes in aged hematopoietic stem cells, molecular players and pathways involved in aged hematopoietic stem cell metabolism, the consequences of perturbed metabolism on clonal hematopoiesis and leukemogenesis, and pharmacologic/ genetic strategies to reverse or rejuvenate altered metabolic phenotypes.

Keywords:  aging; clonal hematopoiesis; hematopoietic stem cell; leukemogenesis; metabolism

DOI:  https://doi.org/10.1152/physiol.00054.2024
Blood Adv. 2025 Mar 06. pii: bloodadvances.2024014901. [Epub ahead of print]

Safety Run-In and Part 1 of GIMEMA AML1718: Venetoclax Combined with FLAI as Induction Treatment in Non-Low-Risk AML.

Giovanni Marconi, Alfonso Piciocchi, Ernesta Audisio, Cristina Papayannidis, Marco Cerrano, Clara Minotti, Francesca Paoloni, Fabio Guolo, Monica Bocchia, Michela Rondoni, Albana Lico, Matteo Giovanni Carrabba, Matteo Giovanni Della Porta, Marco Frigeni, Luisa Giaccone, Germana Beltrami, Chiara Cattaneo, Maria Chiara Di Chio, Bianca Serio, Enrico Crea, Roberto Freilone, Saveria Capria, Antonio Curti, Paola Minetto, Edoardo la Sala, Jacopo Nanni, Beatrice Anna Zannetti, Giorgia Simonetti, Maria Teresa Bochicchio, Giuseppe Saglio, Roberto Massimo Lemoli, Adriano Venditti, Marco Vignetti, Paola Fazi, Giovanni Martinelli.

The standard induction treatment for acute myeloid leukemia (AML) has limited efficacy for patients with non-low-risk AML. We conducted a multicenter study phase 1b/2, GIMEMA AML1718, to investigate the safety and efficacy of venetoclax (VEN) combined with fludarabine, cytarabine, and idarubicin (V-FLAI) as an induction therapy for non-low-risk AML patients younger than 65 years and at intermediate or high ELN risk. After a safety run-in, patients were randomly allocated to VEN 400 mg or VEN 600 mg cohorts. The primary objectives were safety and composite complete remission (bone marrow blasts <5% with any recovery). We report a predefined interim analysis after 57 patients. Median exposure to VEN during induction was 22 days. Effectiveness and safety were similar between VEN 400 mg and VEN 600 mg cohorts. 60-days mortality was 5.8%. Prolonged aplasia was observed in patients receiving high doses of cytarabine during consolidation. cCR, was achieved in 84% of patients. With a median follow-up of 20.6 months, 1-year overall survival was 71%, 1-year disease free survival was 66.2%, 1-year cumulative incidence of relapse was 24%. V-FLAI is an effective induction therapy for young and fit patients. Fifty-five more patients will be enrolled in part 2; they will receive VEN 400 mg-FLAI as predefined and will be centrally evaluated for measurable residual disease. NCT03455504.

DOI: https://doi.org/10.1182/bloodadvances.2024014901
Blood Adv. 2025 Mar 06. pii: bloodadvances.2024015061. [Epub ahead of print]

DNMT3A regulates murine megakaryocyte-biased hematopoietic stem cell fate decisions.

Sarah M Waldvogel, Virginia Camacho, Dandan Fan, Anna Guzman, Alejandra Garcia-Martell, Elmira Khabusheva, Jacey Rodriguez Pridgen, Josephine De La Fuente, Rachel E Rau, Ashlyn Laidman, Maria N Barrachina, Estelle Carminita, Justin Andrew Courson, Michael Williamson, Joanne Ino Hsu, Chun-Wei Chen, Jaime Reyes, Subhashree Pradhan, Rolando Rumbaut, Alan Burns, Benjamin Deneen, Jianzhong Su, Kellie R Machlus, Margaret A Goodell.

Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of the peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but few differential regulatory mechanisms have been identified. In this work, we explored the role of the DNA methyltransferase 3A (DNMT3A) in the megakaryocyte-biased HSC population, which is thought to reside at the top of the hematopoietic hierarchy. We demonstrate that heterozygous loss of DNMT3A (Dnmt3a+/-) in these megakaryocyte-biased HSCs has consequences distinct from the rest of the HSC pool. These megakaryocyte-biased HSCs become delayed in their lymphoid-repopulating ability but can ultimately regenerate all lineages. We further demonstrate that Dnmt3a+/- mice have increased numbers of megakaryocytes in the bone marrow. Analysis of DNA methylation differences between WT and Dnmt3a+/- HSC subsets, megakaryocyte-erythroid progenitors (MEP), and megakaryocytes revealed that DNA methylation is eroded in the mutants in a cell type-specific fashion. While transcriptional differences between the WT and Dnmt3a+/- megakaryocyte-biased HSCs are subtle, the pattern of DNA methylation loss in this HSC subset is almost completely different from that in non-megakaryocyte-biased HSCs. Together, our findings establish the role of epigenetic regulation in the fate of megakaryocyte-biased HSCs and their downstream progeny and suggest that the outcomes of DNMT3A loss might vary depending on the identity of the HSC that acquires the mutation.

DOI: https://doi.org/10.1182/bloodadvances.2024015061
Blood Adv. 2025 Mar 06. pii: bloodadvances.2024014858. [Epub ahead of print]

Transplant Outcomes Using Older Matched Sibling Donors Compared to Young Alternative Donors: A CIBMTR Analysis.

Karthik Nath, Mei-Jie Zhang, Matthew Bye, Muhammad Bilal Abid, Cara Benjamin, Brian C Betts, Neel S Bhatt, Esteban Arrieta-Bolaños, Yung-Tsi Bolon, Shahinaz M Gadalla, Michael R Grunwald, Maxwell M Krem, Stephanie J Lee, Steven G E Marsh, Rodrigo Martino, Parinda A Mehta, Filippo Milano, Timothy Prestidge, Jennifer N Saultz, Bronwen E Shaw, Stephen R Spellman, Hannah K Choe, Brian C Shaffer.

Whether younger donors should be prioritized over HLA-matching for allogeneic hematopoietic cell transplantation (allo-HCT) when using post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis is unclear. To address this, we compared outcomes of allo-HCT recipients aged ≥50-years using PTCy-based GvHD prophylaxis from an older (≥50-years) matched sibling donor (MSD) to those of younger alternative donors ≤35-years: HLA-matched unrelated donors (MUD), HLA-mismatched unrelated donors (MMUD), and haploidentical (haplo)-related donors reported to the Center for International Blood & Marrow Transplant Research between 2014-2021. Young MUD and older MSD receiving calcineurin inhibitor (CNI)-based allo-HCT that met study criteria were concurrently examined. The primary endpoint was overall survival (OS). Among 14,662 HCT recipients, 3,746 received PTCy- and 10,916 CNI-based GvHD prophylaxis. The median follow-up was 47 months. In patients treated with PTCy, the adjusted 5-year OS was not significantly different at 44% for MSD compared with 52% for MUD (multivariable hazard ratio [HR]: 1.20, 95%CI: 1.03-1.41, p=0.09), 45% for haplo (HR: 1.02, 0.88-1.18, p=1.00) and 46% for MMUD (HR: 1.00, 0.83-1.21, p=1.00). Compared to MSDs, receipt of younger MUD associated with improved disease-free survival (DFS) both with PTCy (HR: 1.21, 1.05-1.40, p=0.048) and CNI (HR 1.09, 1.04-1.15, p<0.01) based prophylaxis. Haplo-donor recipients associated with similar OS to MSD, but worse OS compared to MUD recipients with PTCy (HR: 1.18, 1.05-1.33, p=0.04). These data suggest that older MSDs result in similar OS compared to younger alternative donors in older-aged recipients. Younger MUDs may be preferred for older patients due to improved DFS when available.

DOI: https://doi.org/10.1182/bloodadvances.2024014858
Blood Cancer J. 2025 Mar 01. 15(1): 27

Impact of baseline genetic profile and treatment on outcome and hematological toxicity in CEBPA-mutated AML.

Francesco Mannelli, Matteo Piccini, Marco Frigeni, Giacomo Gianfaldoni, Sara Bencini, Silvia Salmoiraghi, Barbara Scappini, Benedetta Peruzzi, Roberto Caporale, Gaia Ciolli, Francesca Crupi, Laura Fasano, Elisa Quinti, Andrea Pasquini, Jessica Caroprese, Fiorenza Vanderwert, Giada Rotunno, Fabiana Pancani, Leonardo Signori, Danilo Tarantino, Chiara Maccari, Francesco Annunziato, Orietta Spinelli, Paola Guglielmelli, Alessandro Rambaldi, Alessandro M Vannucchi.

DOI: https://doi.org/10.1038/s41408-025-01224-w
Blood Adv. 2025 Feb 28. pii: bloodadvances.2024015574. [Epub ahead of print]

BCL11A-deficient human erythropoiesis is impaired in vitro and after xenotransplantation into mice.

Yoonjeong Jang, Ruopeng Feng, Lance E Palmer, Thiyagaraj Mayuranathan, Yu Yao, Kalin Mayberry, Sheng Zhou, Jian Xu, Jeffrey Michael Gossett, Guolian Kang, Yong Cheng, Jonathan S Yen, Mitchell J Weiss.

Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates b-hemoglobinopathies by inducing the fetal g-globin genes. However, additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells using a clinically approved strategy caused impaired expansion and apoptosis of erythroid precursors in vitro and reduced repopulation of the erythroid compartment after xenotransplantation into immunodeficient mice. Mutant colony-forming unit erythroid cells, proerythroblasts and basophilic erythroblasts exhibited dysregulation of 94 genes (> 2-fold change, FDR < 0.05), 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with a range of biological pathways that impact cell expansion and survival. Our findings show that BCL11A regulates additional aspects of erythropoiesis beyond g-globin gene repression, with unknown clinical consequences.

DOI: https://doi.org/10.1182/bloodadvances.2024015574
Nat Aging. 2025 Mar 06.

Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.

Haruhito Totani, Takayoshi Matsumura, Rui Yokomori, Terumasa Umemoto, Yuji Takihara, Chong Yang, Lee Hui Chua, Atsushi Watanabe, Takaomi Sanda, Toshio Suda.

The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.

DOI: https://doi.org/10.1038/s43587-025-00828-y
bioRxiv. 2025 Feb 26. pii: 2025.02.23.639689. [Epub ahead of print]

Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Tsuyoshi Fukushima, Trine Ahn Kristiansen, Lai Ping Wong, Samuel Keyes, Yosuke Tanaka, Michael Mazzola, Ting Zhao, Lingli He, Masaki Yagi, Konrad Hochedlinger, Satoshi Yamazaki, Ruslan I Sadreyev, David T Scadden.

Transitions between subsets of differentiating hematopoietic cells are widely regarded as unidirectional in vivo. Here, we introduce clonal phylogenetic tracer (CP-tracer) that sequentially introduces genetic barcodes, enabling high-resolution analysis of ~100,000 subclones derived from ~500 individual hematopoietic stem cells (HSC). This revealed previously uncharacterized HSC functional subsets and identified bidirectional fate transitions between myeloid-biased and lineage-balanced HSC. Contrary to the prevailing view that the more self-renewing My-HSCs unidirectionally transition to balanced-HSCs, phylogenetic tracing revealed durable lineage bidirectionality with the transition favoring My-HSC accumulation over time1,2. Further, balanced-HSCs mature through distinct intermediates My-HSCs and lymphoid-biased-HSCs with lymphoid competence here shown by CRISPR/Cas9 screening to be dependent on the homeobox gene, Hhex. Hhex enables Ly-HSC differentiation, but its expression declines with age. These findings establish HSC plasticity and Hhex as a determinant of myeloid-lymphoid balance with each changing over time to favor the age-related myeloid bias of the elderly.

DOI: https://doi.org/10.1101/2025.02.23.639689
Genome Biol. 2025 Feb 28. 26(1): 44

CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis.

Xue Yang, Li Cheng, Ye Xin, Jianxiang Zhang, Xinfeng Chen, Jinchao Xu, Mengli Zhang, Ruopeng Feng, Judith Hyle, Wenjie Qi, Wojciech Rosikiewicz, Beisi Xu, Chunliang Li, Peng Xu.

   BACKGROUND: CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, genome-wide impact of CTCF on erythropoiesis has not been extensively investigated.
RESULTS: Using a state-of-the-art human erythroid progenitor cell model (HUDEP-2 and HEL cell lines), we systematically investigate the effects of acute CTCF loss by an auxin-inducible degron system on transcriptional programs, chromatin accessibility, CTCF genome occupancy, and genome architecture. By integrating multi-omics datasets, we reveal that acute CTCF loss notably disrupts genome-wide chromatin accessibility and the transcription network. We detect over thousands of decreased chromatin accessibility regions but only a few hundred increased regions after CTCF depletion in HUDEP-2 and HEL lines, suggesting the role of CTCF in maintaining proper chromatin openness in the erythroid lineage. CTCF depletion in the erythroid context notably disrupts the boundary integrity of topologically associating domains and chromatin loops but does not affect nuclear compartmentalization. We find erythroid lineage-specific genes, including some metabolism-related genes, are suppressed at immature and mature stages. Notably, we find a subset of genes whose transcriptional levels increase upon CTCF depletion, accompanied by decreased chromatin accessibility regions enriched with the GATA motif. We further decipher the molecular mechanism underlying the CTCF/GATA2 repression axis through distal non-coding chromatin regions. These results suggest a suppressive role of CTCF in gene expression during erythroid lineage specification.
CONCLUSIONS: Our study reveals a novel role of CTCF in regulating erythroid differentiation by maintaining its proper chromatin openness and gene expression network, which extends our understanding of CTCF biology.

Keywords:  CTCF; Chromatin accessibility; Erythropoiesis; Genome editing; Hematopoiesis; Transcription regulation

DOI:  https://doi.org/10.1186/s13059-025-03510-z
Eur J Haematol. 2025 Mar 04.

TP53-Mutated Acute Myeloid Leukemia: Review of Treatment and Challenges.

Bipin Ghimire, Markie Zimmer, Vijayalakshmi Donthireddy.

  Patients with acute myeloid leukemia (AML) harboring mutations in TP53 (TP53-MT) have poor responses to current therapies and unfavorable prognoses. Despite the recognition of variant TP53 as an adverse feature of AML, an optimal treatment regimen has not yet been established, underlining a critical need for new, more effective therapeutic combinations and novel treatments. We present the case of a patient with TP53-MT AML and marked myelodysplasia who developed primary refractory disease after induction therapy with the intensive chemotherapy regimen of liposomal daunorubicin and cytarabine. Our patient's optimal response to second induction chemotherapy with FLAG-Ida prompted an exploration of established and investigational treatment regimens for this specific high-risk AML subtype. Therefore, we performed a comprehensive literature review of findings from studies exploring AML therapies, focusing on outcomes for patients with TP53-MT AML. The summary provided here reveals the complexity of defining the therapeutic responses of patients with the heterogeneous TP53-MT genetic background and the challenges in treating this high-risk form of AML. Future work must continue to investigate novel therapies and combinations to improve patient outcomes in this vulnerable population.

Keywords:   TP53 ; acute myeloid leukemia; myelodysplasia; p53

DOI:  https://doi.org/10.1111/ejh.14404
Oncogene. 2025 Mar 04.

WTAP-mediated m6A methylation of PHF19 facilitates cell cycle progression by remodeling the accessible chromatin landscape in t(8;21) AML.

Yu-Qing Li, Di Liu, Li-Li Wang, Yang-Liu Shao, Hui-Sheng Zhou, Ya-Lei Hu, Kai-Li Min, Chun-Ji Gao, Dai-Hong Liu, Jie Zhou, Ji Lin, Xiao-Ning Gao.

Wilms' tumor 1-associated protein (WTAP) is a key N6-methyladenosine (m6A) methyltransferase that is upregulated in t(8;21) acute myeloid leukemia (AML) under hypoxia inducible factor 1α-mediated transcriptional activation, promoting leukemogenesis through transcriptome-wide m6A modifications. However, the specific substrates and intrinsic regulatory mechanisms of WTAP are not well understood. Here, we provide evidence that PHD finger protein 19 (PHF19) overexpression is regulated by WTAP-mediated m6A modification and promotes cell cycle progression by altering chromatin accessibility. At the same time, high expression of PHF19 and WTAP in t(8;21) AML patients indicates a worse prognosis. Furthermore, inhibition of PHF19 expression significantly suppresses the growth of t(8;21) AML cells in both in vitro and in vivo. Mechanistically, WTAP enhances the stability of PHF19 mRNA by binding to m6A sites in the 3'-untranslated region, thereby upregulating PHF19 expression. Conversely, WTAP suppression reduces m6A modification levels on the PHF19 transcript, leading to increased instability. Knockdown of PHF19 precipitates loss of H3K27 trimethylation and enhanced chromatin accessibility, ultimately resulting in upregulated expression of genes involved in the cell cycle and DNA damage checkpoints. Therefore, WTAP/m6A-dependent PHF19 upregulation accelerates leukemia progression by coordinating m6A modification and histone methylation, establishing its status as a novel therapeutic target for t(8;21) AML.

DOI: https://doi.org/10.1038/s41388-025-03329-9
Leuk Lymphoma. 2025 Mar 07. 1-9

Real world efficacy of luspatercept in patients with lower-risk myelodysplastic syndromes/neoplasms (MDS); a single center study in a heavily pretreated cohort.

Marisa L Kometas, Fieke W Hoff, Jonathan Hyak, Vivian Irizarry-Gatell, Alejandro Marinos Velarde, Clayton Jackson, Julia Anderson, Fatma Neslihan Kalkan, Praveen Ramakrishnan Geethakumari, Julio Alvarenga Thiebaud, Weina Chen, Olga K Weinberg, Miguel D Cantu, Robert H Collins, Stephen S Chung, Yazan F Madanat.

  Anemia leads to transfusion dependence and decreases quality of life in LR-MDS patients. Our study retrospectively evaluates the efficacy and safety of luspatercept in the real-world treatment of anemia in LR-MDS, and the impact of patient and disease characteristics on hematologic improvement erythroid (HI-E). Baseline patient and disease characteristics, and transfusion burden (TB) were captured. HI-E was assessed in patients with ≥16 weeks of therapy per IWG 2018 criteria. Luspatercept achieved high rates (58.1%) of transfusion independence (TI) in heavily pretreated LR-MDS patients (median 58.3 weeks). Response was associated with serum EPO <100 mU/ml, but not with any other baseline characteristic. Adverse effects, including shortness of breath, falls, fatigue, and hypertension, precipitated discontinuation in 8%. Eleven percent progressed to HR-MDS or AML. Median overall survival was not reached and did not differ between responders and nonresponders (p=NS).

Keywords:  Myelodysplastic syndromes/neoplasms; luspatercept; ring sideroblasts

DOI:  https://doi.org/10.1080/10428194.2025.2470783
J Clin Invest. 2025 Mar 04. pii: e183607. [Epub ahead of print]

Restoring mitochondrial function promotes hematopoietic reconstitution from cord blood following cryopreservation-related functional decline.

Yaojin Huang, Xiaowei Xie, Mengyao Liu, Yawen Zhang, Junye Yang, Wenling Yang, Yu Hu, Saibing Qi, Yahui Feng, Guojun Liu, Shihong Lu, Xuemei Peng, Jinhui Ye, Shihui Ma, Jiali Sun, Lu Wang, Linping Hu, Lin Wang, Xiaofan Zhu, Hui Cheng, Zimin Sun, Junren Chen, Fang Dong, Yingchi Zhang, Tao Cheng.

  Umbilical cord blood (UCB) showcases substantial roles in hematopoietic stem cells (HSCs) transplantation and regenerative medicine. UCB is usually cryopreserved for years before use. Whether and how cryopreservation affects its function remain unclear. We constructed single-cell transcriptomic profile of CD34+ hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) from fresh and cryopreserved UCB stored for 1-, 5-, 10-, and 19- years. Compared to fresh UCB, cryopreserved HSCs and multipotent progenitors (MPPs) exhibited more active cell cycle and lower HSC/MPP signature gene expressions. Hematopoietic reconstitution of cryopreserved HSPCs gradually decreased during the first 5 years but stabilized thereafter, aligning with the negative correlation between clinical neutrophil engraftment and cryopreservation duration of UCB. Cryopreserved HSPCs also showed reduced megakaryocyte generation. In contrast, cryopreserved natural killer (NK) cells and T cells maintained cytokine production and cytotoxic ability comparable to fresh cells. Mechanistically, cryopreserved HSPCs exhibited elevated reactive oxygen species, reduced ATP synthesis, and abnormal mitochondrial distribution, which collectively led to attenuated hematopoietic reconstitution. These effects could be ameliorated by sulforaphane. Together, we elucidated the negative impact of cryopreservation on UCB HSPCs and provided sulforaphane as a mitigation strategy, broadening the temporal window and scope for clinical applications of cryopreserved UCB. .

Keywords:  Hematology; Hematopoietic stem cells; Stem cells

DOI:  https://doi.org/10.1172/JCI183607
bioRxiv. 2025 Feb 17. pii: 2025.02.17.638713. [Epub ahead of print]

SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer.

Peiqi Xing, Pedro Bak-Gordon, Jindou Xie, Jian Zhang, Zhaoqi Liu, James L Manley.

SF3B1 is the most frequently mutated splicing factor in cancer. Mechanistically, such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulated mutant SF3B1 splicing dysregulation. Strikingly, our analysis revealed only two proteins whose loss reproduced this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulated almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduced ∼40% of these defects. However, we found that AQR knockdown caused significant SUGP1 missplicing and reduced protein levels, suggesting that AQR loss reproduced mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic SF3B1 mutations, and highlights the fundamental role of SUGP1 in this process.

DOI: https://doi.org/10.1101/2025.02.17.638713
Nat Commun. 2025 Mar 04. 16(1): 2191

A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.

Guillaume P Andrieu, Mathieu Simonin, Aurélie Cabannes-Hamy, Etienne Lengliné, Ambroise Marçais, Alexandre Théron, Grégoire Huré, Jérome Doss, Ivan Nemazanyy, Marie Émilie Dourthe, Nicolas Boissel, Hervé Dombret, Philippe Rousselot, Olivier Hermine, Vahid Asnafi.

The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.

DOI: https://doi.org/10.1038/s41467-025-57225-7
Cancer Discov. 2025 Mar 05. OF1-OF5

Tackling Cancer through Global Team Science.

Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott.

Here, we discuss the seven new challenges set by Cancer Grand Challenges that are currently open for creative applications. We invite the research community to assemble global, interdisciplinary teams to tackle these challenges and ultimately change the way we think about, study, prevent, and treat cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0282
Leukemia. 2025 Mar 05.

Management of children and adolescents with chronic myeloid leukemia in chronic phase: International pediatric chronic myeloid leukemia expert panel recommendations.

Frédéric Millot, Mirella Ampatzidou, Nirmalya Roy Moulik, Sanjay Tewari, Alaa Elhaddad, Mahmoud Hammad, Herbert Pichler, Thomas Lion, Athanasios Tragiannidis, Haruko Shima, Wenbin An, Wenyu Yang, Axel Karow, Roula Farah, Maaike Luesink, Michael Dworzak, Stephanie Sembill, Barbara De Moerloose, Petr Sedlacek, Kirk R Schultz, Krzysztof Kalwak, Birgitta Versluys, Uma Athale, Nobuko Hijiya, Markus Metzler, Meinolf Suttorp.

The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.

DOI: https://doi.org/10.1038/s41375-025-02543-4