bims-tremyl 2026-01-04 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–01–04
nineteen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.
A Stem and Progenitor Cell-Derived Gene Expression Signature is Prognostic for Survival in Myelofibrosis.
NFE2 Truncation Mutants Protect Wild-Type NFE2 from ITCH-Dependent Degradation.
Outcomes of Patients With IDH1-Mutated Myeloid Neoplasms Treated With Olutasidenib.
Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.
Impact of Germline DNA Repair Mutations on Clonal Hematopoiesis and Myeloid Neoplasm Development.
Pandora's Box of AML: How TP53 Mutations Defy Therapy and Hint at New Hope.
Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging.
Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators.
Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines leukemic cells with Migratory Potential.
Comprehensive Molecular and Functional Analysis of NUTM1-Rearranged Leukemia.
Ultraprecision Therapy for Type 1 vs Type 2 CALR+ MPN by Dual Epitope Targeting that Restores Ruxolitinib Sensitivity.
Menin inhibitors for adult acute myeloid leukemia: 2025 update.
Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.
Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.
Enterococcus induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease.
Health-related quality of life and symptom profile of patients with BCR::ABL1-negative myeloproliferative neoplasms: Real-world evidence from the GIMEMA-PROPHECY observational study.
p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.

Science. 2026 Jan;391(6780): 52-58

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.

Gaurav Agarwal, Mateusz Antoszewski, Xueqin Xie, Yash Pershad, Uma P Arora, Chi-Lam Poon, Peng Lyu, Andrew J Lee, Chun-Jie Guo, Tianyi Ye, Laila Barakat Norford, Anna-Lena Neehus, Lucrezia Della Volpe, Lara Wahlster, Diyanath Ranasinghe, Tzu-Chieh Ho, Trevor S Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, Benjamin H Durham, Omar Abdel-Wahab, Kathy L McGraw, James M Allan, Ruslan Soldatov, Alexander G Bick, Michael G Kharas, Vijay G Sankaran.

Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1-mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.

DOI: https://doi.org/10.1126/science.adx4174
Cell Rep Med. 2025 Dec 29. pii: S2666-3791(25)00599-3. [Epub ahead of print] 102526

CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.

Melissa L Stewart, Jessica Gibbs, Kevin Watanabe-Smith, Ariel Nguyen, Isabel Kenna, Karina Thiel-Klare, Andy Kaempf, Daniel Bottomly, Stephen E Kurtz, Christopher A Eide, Nicola Long, Jennifer N Saultz, Luca Sax, Ariane Huang, Shannon K McWeeney, Bill H Chang, Jeffrey W Tyner.

  Venetoclax (ven) combined with azacytadine is a widely used therapy for acute myeloid leukemia (AML). However, most patients develop resistance. To identify more effective combinations, we analyze 302 AML patient samples and find ven plus palbociclib (ven+palbo), a cyclin dependent kinase (CDK)4/6 inhibitor, to be highly effective. Ven+palbo shows synergistic activity in AML cell lines and patient-derived xenograft mouse models. Patient samples exhibiting a synergistic response to ven+palbo show downregulation of genes involved in protein synthesis. Genome-wide (CRISPR) screening shows that loss of translational genes uniquely confers sensitivity to ven but not to ven+palbo. AML cells exposed to ven exhibit an adaptive increase of protein synthesis that is overcome by ven+palbo through regulation of translational machinery. Additionally, ven+palbo mitigates resistance mechanisms observed with single-agent ven (BAX loss) and palbo (RB1 loss). Finally, we identify the loss of IKZF1 as a mechanism of resistance to ven+palbo and show that targeting AXL is effective in IKZF1-mutated AML.

Keywords:  cell state; monocytic; progenitor; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2025.102526
Blood. 2026 Jan 02. pii: blood.2025030094. [Epub ahead of print]

A Stem and Progenitor Cell-Derived Gene Expression Signature is Prognostic for Survival in Myelofibrosis.

Jessie J F Medeiros, Andy G X Zeng, Suraj Bansal, Hyerin Kim, Michelle Chan-Seng-Yue, Tristan Woo, Jessica L McLeod, Sagar Kothari, Andrea Arruda, Hubert Tsui, Jaime O Claudio, Dawn Maze, Hassan Sibai, Mark D Minden, James A Kennedy, Christopher A Famulare, Raajit K Rampal, Jean C Y Wang, John E Dick, Vikas Gupta.

We hypothesized that transcriptomic features among disease-driving hematopoietic stem and progenitor cells (HSPC) could improve the current paradigm for risk stratification in myelofibrosis (MF). Therefore, we performed bulk RNA-seq on blood from 358 MF patients split into training and test cohorts (ClinicalTrials.gov Identifier: NCT02760238). Single-cell (sc) RNA-seq data from Lin-CD34+ MF HSPCs were used to guide the development of a prognostic model trained on the bulk RNA-seq data. A NanoString assay was used to validate our final model in two independent cohorts of MF patients. We identified a 24-gene weighted-sum expression score (termed MPN24) that was prognostic of overall survival (OS). In two independent cohorts of 170 and 100 MF patients, MPN24-High scoring patients had worse 5-year OS compared to MPN24-Low scoring patients (25.5% vs 86.9%, HR = 9.81, P = 4.0e-11 and 23.5% vs 75.9%, HR = 6.40, P = 1.8e-7, respectively). MPN24-High was also associated with clinical, mutation and karyotypic features known to confer adverse risk in MF. The MPN24 score retained independent prognostic significance in multivariable analysis incorporating these covariates as well as existing risk stratification models including DIPSS, DIPSS Plus, MIPSS70, and MIPSS70 Plus v2.0, adding significant prognostic value to these risk stratification models (P = 1.6e-5, 4.0e-6, 1.5e-6, 5.4e-4, respectively). The MPN24 score was particularly useful in improving risk-stratification of DIPSS-Intermediate, and MIPSS70 Intermediate and High-risk patients. MPN24 is an HSPC-derived gene expression score that is associated with overall survival independent of clinical and genomic prognostic variables and improves risk stratification in MF.

DOI: https://doi.org/10.1182/blood.2025030094
Int J Mol Sci. 2025 Dec 16. pii: 12112. [Epub ahead of print]26(24):

NFE2 Truncation Mutants Protect Wild-Type NFE2 from ITCH-Dependent Degradation.

Mirjam Elisabeth Hoeness, Franziska Zell, Titiksha Basu, Katharina Gellrich, Albert Gründer, Jana Schulze, Anja Müller, Philipp Eble, Christoph Koellerer, Anne Marie Staehle, Sarolta Bojtine Kovacs, Heike L Pahl, Hans Felix Staehle.

  Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the abnormal proliferation of myeloid cells. In addition to the main driver mutations in JAK2, MPL, and CALR, the transcription factor nuclear factor erythroid 2 (NFE2) has emerged as a key contributor to MPN pathophysiology. NFE2 expression is elevated in the majority of MPN patients, and augmented NFE2 activity in hematopoietic stem cells is sufficient to induce an MPN phenotype with spontaneous leukemic transformation in murine models. Moreover, NFE2 mutations, found in a subset of MPN patients, augment NFE2 activity and are associated with a markedly increased risk of progression to acute myeloid leukemia (AML). However, the molecular mechanism by which NFE2 mutations cause leukemogenesis is not understood. Here, we demonstrate that the E3 ubiquitin ligase ITCH mediates proteasomal degradation of wild-type (wt) NFE2 in HEK-293T cells. A gain-of-function truncation mutant, NFE2-226aa, retains the capacity to interact with ITCH but is no longer degraded. Rather, NFE2-226aa protects wt NFE2 from ITCH-dependent degradation, resulting in enhanced NFE2 activity.

Keywords:  ITCH; MPN; NFE2

DOI:  https://doi.org/10.3390/ijms262412112
Clin Lymphoma Myeloma Leuk. 2025 Dec 10. pii: S2152-2650(25)04296-X. [Epub ahead of print]

Outcomes of Patients With IDH1-Mutated Myeloid Neoplasms Treated With Olutasidenib.

Kelly S Chien, Sanam Loghavi, Koji Sasaki, Deborah McCue, Naval G Daver, Tapan M Kadia, Farhad Ravandi, Nicholas J Short, Ghayas C Issa, Guillermo Montalban-Bravo, Fadi G Haddad, Danielle E Hammond, Mahesh Swaminathan, Alexandre Bazinet, Alex Bataller, Ian Bouligny, Sherry A Pierce, Guillermo Garcia-Manero, Hagop M Kantarjian, Courtney D DiNardo.

   BACKGROUND: IDH1 mutations correlate with poor prognosis in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), though this has evolved with targeted therapy. Olutasidenib, a selective oral IDH1 inhibitor, was approved for relapsed/refractory (R/R) AML in 2022.
METHODS: We investigated a single-institution experience with olutasidenib regimens in IDH1-mutated AML and MDS.
RESULTS: The study included 24 patients (19 AML, 5 MDS), with median age 75 years and 15 (62%) males. Fifteen patients (79%) had adverse-risk AML; 5 (100%) higher-risk MDS; and 9 (47%) secondary AML. The AML and MDS groups each included 2 previously untreated patients. The 17 R/R AML patients received a median of 3 prior therapies, including ivosidenib and/or venetoclax. Patients received olutasidenib monotherapy (n = 8) or combination therapy (n = 16). All 4 previously untreated patients responded. Overall response rates were 35% in R/R AML and 33% in R/R MDS. Two AML patients in complete remission remain on olutasidenib 5 to 7 years later, and 2 underwent allogeneic stem cell transplant. In the R/R patients, median overall survival was 3.3 months in AML and 14.0 months in MDS. Prior ivosidenib or venetoclax exposure did not impact survival.
CONCLUSION: Olutasidenib-based therapy demonstrated 100% response rates in previously untreated IDH1-mutated AML and MDS and modest efficacy in heavily pretreated R/R AML and MDS. Durable remissions occurred in select responders and with stem cell transplant. Further evaluation of olutasidenib as frontline therapy in IDH1-mutated AML or MDS and as a bridge to transplant is warranted.

Keywords:  AML; Acute myeloid leukemia; IDH1,MDS; Myelodysplastic syndromes

DOI:  https://doi.org/10.1016/j.clml.2025.12.001
J Clin Invest. 2025 Dec 30. pii: e184285. [Epub ahead of print]

Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.

Sisi Chen, Sergio Barajas, Sasidhar Vemula, Yuxia Yang, Ed Simpson, Hongyu Gao, Rudong Li, Farzaneh Behzadnia, Sarah C Nabinger, David A Schmitz, Hongxia Chen, Wenjie Cai, Shiyu Xiao, Ruyue Luo, Mohammed Abdullahel Amin, Maegan L Capitano, James P Ropa, Aidan Fahey, Shuyi Zhou, Tiffany M Mays, Magdalena Sotelo, Hao Pan, Sophie K Hu, Sophia Veranga, Moiez Ali, Maria Shumilina, Reuben Kapur, Kehan Ren, Yuzhi Jia, Huiping Liu, Irum Khan, Yasmin Abaza, Jessica K Altman, Elizabeth A Eklund, Lucy A Godley, Christine R Zhang, Peng Ji, Seth L Masters, Ben A Croker, H Scott Boswell, George E Sandusky, Zhonghua Gao, Lindsey D Mayo, Sharon A Savage, Stephanie Halene, Yali Dou, Leonidas C Platanias, Madina Sukhanova, Yunlong Liu, Omar Abdel-Wahab, Yan Liu.

  Aged individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting wild type (WT) HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D (GSDMD) inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant clonal hematopoiesis to myeloid neoplasms.

Keywords:  Cytokines; Hematology; Hematopoietic stem cells; Inflammation; NF-kappaB

DOI:  https://doi.org/10.1172/JCI184285
Curr Hematol Malig Rep. 2025 Dec 29. 20(1): 24

Impact of Germline DNA Repair Mutations on Clonal Hematopoiesis and Myeloid Neoplasm Development.

Kateryna Fedorov, Leo Y Luo, Alexander G Bick, Michael R Savona.

   PURPOSE OF REVIEW: Clonal hematopoiesis (CH) arises from the expansion of a single hematopoietic stem cell harboring somatic mutations that confer growth advantage. Recent studies highlight a substantial heritable component to CH, implicating germline mutations in DNA damage repair (DDR) genes. These genes are essential for maintaining genomic integrity and pathogenic variants in key DDR genes are well-established genetic underpinnings of several hereditary cancer syndromes. This review synthesizes current data linking germline DDR mutations - including ATM, CHEK2, TP53, PPM1D, BRCA1/2, and PARP1 - to CH and the development of myeloid malignancies.
RECENT FINDINGS: Emerging evidence suggests that germline perturbations in DDR pathway contribute to CH, though mechanisms remain incompletely defined. Large scale genome-wide association studies (GWAS) have identified strong associations between ATM and CHEK2 variants and CH. Assessing prevalence and CH risk in individuals with germline TP53 variants presents unique challenges, as distinguishing between somatic and constitutional lesions is often complex and requires careful tissue evaluation. The link between germline BRCA1/2 and CH remains inconclusive, confounded by concurrent diagnosis of solid malignancy and prior exposure to chemoradiation therapy in studied patient populations. Although germline mutations in PPM1D and PARP1 are rare, a potential germline predisposition to CH cannot be excluded. The totality of current evidence suggests that germline DDR pathway mutations not only predispose to well-established solid malignancy syndromes but also to CH, which independently increases the risk of hematologic malignancies. Recognizing germline contributions to CH has broad implications for risk assessment, surveillance strategies, and development of preventive strategies in myeloid neoplasia.

Keywords:   Clonal hematopoiesis; DNA Damage Repair mutations; Germline predisposition; Myeloid Neoplasms

DOI:  https://doi.org/10.1007/s11899-025-00768-9
Biomedicines. 2025 Dec 08. pii: 3007. [Epub ahead of print]13(12):

Pandora's Box of AML: How TP53 Mutations Defy Therapy and Hint at New Hope.

Elyse A Olesinski, Shruti Bhatt.

  TP53 mutations are among the worst prognostic factors in acute myeloid leukemia (AML), with affected patients facing relapse-free survival of just five-to-six months compared to TP53 wild-type patients. A major barrier to improving outcomes lies in the dearth of effective therapies, as TP53 mutant patients remain refractory to conventional cytotoxic chemotherapies, targeted therapies, and even allogeneic stem cell transplantation. In this review, we first summarize current clinical strategies and the major setbacks of p53 activators, MDM2/X regulators, and immunotherapy, highlighting the disconnect between promising pre-clinical studies and limited durable clinical responses. We next discuss the mechanisms of therapy resistance in TP53 mutant AML, with specific emphasis on dysfunction in the mitochondrial apoptotic pathway and clonal evolution of TP53 mutant hematopoietic stem cells. We then outline a roadmap for developing tailored therapies that may finally redefine prognosis for this high-risk patient population, including apoptotic activators, cell-cycle modulators, and immune- and metabolic-based therapies. We lastly call attention to new biomarker-driven approaches that can improve patient stratification and optimize identification of responders. By connecting mechanistic understanding with translational insights, this review underscores both the formidable challenges and the emerging opportunities in TP53 mutant AML.

Keywords:  AML; TP53 mutations; therapy resistance

DOI:  https://doi.org/10.3390/biomedicines13123007
J Exp Med. 2026 Feb 02. pii: e20251805. [Epub ahead of print]223(2):

Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging.

Emanuele Lettera, Luca Basso-Ricci, Edoardo Carsana, Kety Giannetti, Teresa Tavella, Luca Seffin, Giacomo Farina, Nicolò Gualandi, Pamela Quaranta, Elena Lo Furno, Guido Pacini, Lucrezia Della Volpe, Kerstin B Kaufmann, Laura Garcia-Prat, Raisa Jofra Hernandez, Alex Murison, Alicia G Aguilar-Navarro, Stefano Beretta, Anastasia Conti, Eugenia Flores-Figueroa, Marco Ometti, Ivan Merelli, Alessandro Aiuti, Stephanie Z Xie, Serena Scala, Raffaella Di Micco.

Hematopoietic stem/progenitor cells (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPCs from older individuals exhibited repopulating frequencies comparable with those from younger donors in both primary and secondary xenografts; however, aged HSCs displayed impaired differentiation, chromatin and cell cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features after xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress-based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions.

DOI: https://doi.org/10.1084/jem.20251805
Sci Adv. 2026 Jan 02. 12(1): eadu8292

Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators.

Aristeidis G Telonis, Robert F Stanley, Emmalee R Adelman, Akihide Yoshimi, Adedamola A Adele, Angelique Cruz, Daniel H Wiseman, Omar Abdel-Wahab, Maria E Figueroa.

Genes affecting DNA methylation (DNAme) are frequently comutated with splicing factors in acute myeloid leukemia (AML) and associate with more aggressive phenotypes. To elucidate the underlying molecular mechanisms, we deeply profiled wild-type and IDH2R140Q/SRSF2P95 single- or double-mutant AMLs. We find a unique set of mis-spliced genes and differentially methylated CpGs in double mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap footprints of RNA binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the complexes regulating these differentially expressed genes. Thus, aberrant DNAme and splicing lead to the mis-splicing of key regulatory complexes, resulting in the aberrant gene expression profiles characteristic of these AMLs.

DOI: https://doi.org/10.1126/sciadv.adu8292
Exp Hematol. 2025 Dec 25. pii: S0301-472X(25)00642-3. [Epub ahead of print] 105363

Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines leukemic cells with Migratory Potential.

Elsa Görsch, Saskia Rudat, Marlon Arnone, Hildegard Keppeler, Nandini Asokan, Jan C Schröder, Taylor Scott Mills, Lucas Mix, Lea Kramer, Jan Pauluschke-Fröhlich, Maksim Klimiankou, Jan Weller, Gerd Klein, Claudia Lengerke.

  Interactions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptors with stemness in healthy hematopoiesis, their role in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin α3β1, α6β1, α7β1 and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high mRNA expression of all four laminin receptors correlates with poor overall survival. Notably, integrin α6 and α7 display the highest cell surface density among the examined laminin receptors and are higher expressed on AML cells compared to healthy controls. Moreover, our results indicate that the absence of integrin α7 expression can identify cells with increased colony forming potential, even in patients that are negative for the stem cell marker CD34 usually used to enrich LSC. Re-analyzing survival data from the TCGA-AML cohort, integrin α7 expression further allows refinement of the risk stratification based on the LSC score where low LSC and integrin α7 levels confer superior survival. Lastly, integrin α7 appears to mark leukemic cells with enhanced migratory potential, which can be inhibited by the anti-integrin α7 blocking antibody in vitro and in vivo. Together, our results confirm the association of high laminin receptor expression with poor prognosis, and establish integrin α7 as marker of high migratory leukemic cells. TEASER ABSTRACT: Acute myeloid leukemia (AML) cells engage with supportive bone marrow niche cells and extracellular matrix (ECM) proteins through surface receptors. Here, we demonstrate that high mRNA expression of the laminin receptors integrin α3β1, α6β1, α7β1 and BCAM correlates with poor overall survival. Moreover, integrin α7 expression marks leukemic cells displaying enhanced migratory potential. Together, we believe that our study significantly advances our understanding of AML-ECM interactions, and provides important insights that might be instrumental in the development of future therapies addressing therapy resistance in AML.

Keywords:  acute myeloid leukemia; bone marrow niche; integrin α7β1; laminin receptors; leukemic stem cells; migration and homing

DOI:  https://doi.org/10.1016/j.exphem.2025.105363
Blood. 2025 Dec 29. pii: blood.2024026928. [Epub ahead of print]

Comprehensive Molecular and Functional Analysis of NUTM1-Rearranged Leukemia.

Koutarou Nishimura, Tomoya Isobe, Tsukasa Shigehiro, Masaki Nomura, Weijia Zang, Muran Xiao, Wenjuan Liao, Yui Koike, Akira Nishimura, Aiko Sato-Otsubo, Hiromi Yamazaki, Hiromi Ito, Shinri Okada, Naomi Matsumoto, Wataru Saika, Yifan Zhang, Yumi Aoyama, Chihiro Hasegawa, Takaya Yamasaki, Yasuo Kubota, Kentaro Oki, Nobutaka Kiyokawa, Genta Nagae, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Mariko Eguchi, Yuki Arakawa, Katsuyoshi Koh, Takao Deguchi, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Satoru Miyano, Hiroyuki Aburatani, Seishi Ogawa, Akifumi Takaori-Kondo, Akihiko Yokoyama, Omar Abdel-Wahab, Patricia Ernst, Junko Takita, Tomokatsu Ikawa, Masatoshi Takagi, Daichi Inoue.

NUTM1-rearrangement (NUTM1-r) defines a significant subset of B-cell acute lymphoblastic leukemia (B-ALL), particularly in infants lacking KMT2A-rearrangements (KMT2A-r), yet its underlying molecular characteristics remain poorly understood. Here, we establish that NUTM1-r leukemia is a discrete entity characterized by a unique transcriptional and epigenetic landscape, notably featuring global DNA hypomethylation, irrespective of the 5' fusion partner. Functional interrogation of NUTM1 fusions reveals a dual oncogenic role: they drive commitment towards the B-lymphoid lineage while concurrently conferring potent leukemic stem cell properties. Strikingly, expression of a representative fusion, BRD9-NUTM1, is sufficient to induce serially-transplantable prepro-B-like leukemia in vivo, faithfully recapitulating the key molecular and immunophenotypic features of human NUTM1-r B-ALL. Mechanistically, NUTM1 fusions establish an aberrant chromatin state, marked by global enhancement of H3K27 acetylation and the creation of distinctive open chromatin regions that co-opt both B-lineage and stemness-related transcriptional programs, including those involving NF-κB and posterior HoxA genes. In stark contrast to resistant KMT2A-r leukemias, NUTM1-r leukemic cells exhibit a profound sensitivity to chemotherapy. This vulnerability is mechanistically linked to the leukemia's dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, revealing specific vulnerabilities that rationalize their favorable clinical outcomes and suggest opportunities for modified therapeutic strategies.

DOI: https://doi.org/10.1182/blood.2024026928
Blood. 2026 Jan 02. pii: blood.2024027897. [Epub ahead of print]

Ultraprecision Therapy for Type 1 vs Type 2 CALR+ MPN by Dual Epitope Targeting that Restores Ruxolitinib Sensitivity.

Chloe Al Thompson-Peach, Daniel Thomas, Mara Dottore, Kelly Lim, Frank Stomski, Romana Panagopoulos, Johannes Foßelteder, Andreas Reinisch, Vashe Chandrakanthan, Sandra Jenkner, Luke Bland, Sharon Paton, Stan Gronthos, Timothy Hercus, Hannah Wardill, Winnie L Kan, Maha Kamel, Paul A Moretti, Stuart M Pitson, Kate Burbury, David Morrall Ross, Pramod Nair, Angel F Lopez, Denis Tvorogov.

Somatic frameshift mutations in the gene encoding calreticulin (CALR) give rise to myelofibrosis and are classified as Type 1 (del52) or Type 2 (ins5) according to the degree of wildtype sequence retained adjacent to the neopeptide, with each type conferring different clinical outcomes. Targeting strategies specific for Type 1 vs Type 2 mutations would have enormous clinical utility in the treatment and prevention of myelofibrosis as responses to tyrosine kinase inhibitors are not durable nor mutation-specific. Here we show that dual targeting of Type 1 (del52) mutant CALR with two monoclonal antibodies directed against distinct epitopes in CALR have significant advantages compared to single agent treatment in the eradication of primary megakaryocyte progenitors in vitro and in a humanized ossicle microenvironment leading to improved survival in xenograft models. Dual targeting was superior in blocking constitutive STAT5 and ERK phosphorylation induced by del52 and prevented accumulation of JAK2 phosphorylation, overcoming ruxolitinib resistance. In contrast, Type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting but could be impacted by ruxolitinib triple combination. Together, our data demonstrate an ultra-precision medicine approach tailored to either Type 1 OR Type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signalling, with far-reaching implications for patient management.

DOI: https://doi.org/10.1182/blood.2024027897
Expert Opin Investig Drugs. 2025 Dec 31.

Menin inhibitors for adult acute myeloid leukemia: 2025 update.

Umar Iqbal, Julia Fadul, David A Sallman, Rory M Shallis.

   INTRODUCTION: Menin inhibitors are a relatively new class of drugs that reverse oncogenesis and induce leukemic cell differentiation by blocking the interaction between the MEN1 gene product (menin) and lysine (K)-methyltransferase 2 (KMT2A). This is relevant in 50-70% of acute myeloid leukemia (AML) subsets driven by overexpression of the HOXA9/MEIS1 pathway. These patients have dismal outcomes with current options, especially in the relapsed/refractory setting.
AREAS COVERED: Here, we discuss menin pathobiology, the available and emerging clinical data for menin inhibitors, clinical nuance related to their use, and the current unmet needs that may guide future endeavors for this drug class. A literature search was conducted using PubMed/MEDLINE, Embase and Web of Science databases. The search included articles published in English up to 25 August 2025. Keywords and Medical Subject Headings (MeSH) related to 'menin inhibitors' were combined using Boolean operators (AND, OR). Additionally, abstracts from major hematology conferences were reviewed and the clinicaltrials.gov registry was queried for active trials as well.
EXPERT OPINION: Menin inhibitor approval/use is expanding into other HOX-driven subtypes (e.g. NPM1, NUP98r), as frontline option and in combination settings. Monitoring for differentiation syndrome, QT interval prolongation, recognizing pseudo-progression, and supportive care needs remains essential to maximize patient benefit.

Keywords:  AML; Acute myeloid leukemia; BN-104; bleximenib; enzomenib; menin; revumenib; ziftomenib

DOI:  https://doi.org/10.1080/13543784.2025.2612321
Stem Cell Reports. 2025 Dec 26. pii: S2213-6711(25)00355-8. [Epub ahead of print] 102751

Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.

Ting Song, Yang Song, Hong Zhang, Zhiyuan Hu, Fangkui Yin, Maojun Jiang, Yanxin Zhang, Ziqian Wang, Zhichao Zhang.

  In chronic myeloid leukemia (CML), disease persistence in patients is maintained by leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance. Autophagy has been proposed as a potential therapy to eradicate CML LSCs. Here, using a small-molecule inhibitor of Hsp70 (heat shock protein 70)-Bim (Bcl-2-interacting mediator of cell death) interaction, S1-10, we demonstrate that Hsp70-Bim is a target for CML stemness maintenance. Hsp70-Bim is driven by Bcr-Abl and mediates particularly stronger mitophagy in CML LSCs than differentiated CML cells and HSCs. The more selective mitophagy regulation of Hsp70-Bim than ULK1 (unc-51-like autophagy activating kinase 1) is illustrated. Pharmacological inhibition of Hsp70-Bim blocks mitophagy, leading to the differentiation of CML LSCs, loss of quiescence, and loss of LSC self-renewal potential. In the patient-derived xenograft (PDX) CML models, S1g-10 reduces the number of LSCs by more than 80% after two weeks of injection, without obvious toxicity on normal red blood cells.

Keywords:  Hsp70-Bim; chronic myeloid leukemia; leukemia stem cells; mitophagy; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.stemcr.2025.102751
Nat Aging. 2026 Jan 02.

Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.

Tongyao Shang, Li Zhao, Shibo Ying, Lida Su, Yue Yang, Jiadong Liu, Yingying Wang, Jipeng Xue, Cheng Cheng, Yixin Wu, Shiyao Chen, Hongmei Dong, Xuequn Chen, Hailin Ma, Qi Zhang, Tingbo Liang, Wei Yang, Ye Feng, Marong Fang, Xinjiang Lu.

Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to induce HSC proliferation and myelopoiesis. We show that shear stress induces PIEZO1-mediated ion currents and Ca2+ influx in both mouse and human HSCs, with downstream effects on proliferation and myeloid differentiation mediated via JAM3 and CAPN2 pathways. GsMTx4, a PIEZO1 antagonist, attenuated inflammation-induced aging in mice by inhibiting HSC activation. These findings link the mechanical sensor PIEZO1 to HSC proliferation and myeloid differentiation via multi-tiered signaling, highlighting its role in accelerating inflammation-induced aging.

DOI: https://doi.org/10.1038/s43587-025-01039-1
Blood. 2025 Dec 29. pii: blood.2024028248. [Epub ahead of print]

Enterococcus induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease.

Chi Nguyen, Jennifer Funes, Romina Ghale, Nathan Duong, Kristen Victor, Brianna Gipson, Zhenrun J Zhang, Anqi Dai, Rita Li, Gabriel K Armijo, Ashley S Huang, Miriam Martinez, Yuqing Chen, Daniel Mousa Ghazarian, Melissa D Docampo, Khyatiben V Pathak, Patrick Pirrotte, Kate A Markey, Jonathan U Peled, Jenny Paredes, Marina Burgos da Silva, Marcel R M van den Brink.

Intestinal Enterococcus domination has been associated with an increased risk of mortality by acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigate the interactions between Enterococcus and the intestinal epithelium as a mechanism to aggravate GVHD. We observed that endogenous intestinal Enterococcus outgrowth was associated with increased GVHD mortality and major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells (IECs) in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of non-transplanted gnotobiotic mice with E. faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of four anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E. faecalis colonization also induced inflammatory responses in CD4+ T cells and NK cells from the colonic lamina propria, the two main sources of interferon-gamma production that drives MHC-II expression in non-professional antigen-presenting cells. We further explored the potential therapeutic benefit of establishing colonization resistance against E. faecalis through administration of a lantibiotic-producing B. producta strain after allo-HCT. Colonization of transplanted mice with a consortium of commensal bacteria containing the lantibiotic-producing B. producta strain prevented intestinal Enterococcus domination post-transplant and improved GVHD survival. Our results demonstrate a potential mechanism by which Enterococcus aggravates GVHD through increased MHC-II expression in the intestinal epithelium. Targeting the Enterococcus-epithelium-MHC-II axis thus presents a therapeutic opportunity to prevent lethal GVHD.

DOI: https://doi.org/10.1182/blood.2024028248
Hemasphere. 2025 Dec;9(12): e70274

Health-related quality of life and symptom profile of patients with BCR::ABL1-negative myeloproliferative neoplasms: Real-world evidence from the GIMEMA-PROPHECY observational study.

Giovanni Caocci, Alessandro Costa, Francesca Palandri, Paola Guglielmelli, Andrea Patriarca, Alessandra Iurlo, Alessia Tieghi, Elisabetta Abruzzese, Thomas Baldi, Elena Rossi, Eloise Beggiato, Monia Marchetti, Carmen Fava, Simona Tomassetti, Elisa Rumi, Claudio Fozza, Mario Luppi, Fabrizio Pane, Sara Bigliardi, Massimo Breccia, Elena Maria Elli, Francesca Tartaglia, Olga Mulas, Paola Fazi, Marco Vignetti, Alessandro Maria Vannucchi, Fabio Efficace.

Health-related quality of life (HRQoL) of patients with myeloproliferative neoplasms (MPNs) may be impaired across several domains. In this multicenter observational study, we evaluated HRQoL and symptoms in a cohort of MPN patients with validated measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) questionnaire. The primary objective was to compare the HRQoL profile of patients, by disease subtype, with that of the general population according to the EORTC QLQ-C30. A total of 572 patients with essential thrombocythemia (ET, n = 228), polycythemia vera (PV, n = 207), and myelofibrosis (MF, n = 137) were assessed. Worse statistically and clinically significant differences were observed for role functioning (ET: ∆ = 8.9, P < 0.001; PV: ∆ = 11, P < 0.001; MF: ∆ = 16.7, P < 0.001) and fatigue (ET: ∆ = 5, P < 0.001; PV: ∆ = 8.3, P < 0.001; MF: ∆ = 11.5, P < 0.001) in all three diagnostic groups. However, patients with MF also reported impairments in other important health domains. Fatigue was the most frequently reported and burdensome symptom, with greater severity correlating with a broader and more complex array of associated symptoms. Our analysis also revealed a substantial underestimation of symptoms by treating hematologists in paired physician-patient reports. Current findings may help to disentangle specific HRQoL limitations and symptomatology experienced by patients with MPNs, and underscore the importance of incorporating patient-reported outcomes into routine practice to better reflect the patient's perspective of the disease and treatment-related burden.

DOI: https://doi.org/10.1002/hem3.70274
Nat Genet. 2025 Dec 29.

p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.

Kathrin Laue, Sabina Pozzi, Johanna Zerbib, Rebecca Bertolio, Yonatan Eliezer, Yael Cohen-Sharir, Tom Winkler, Manuel Caputo, Alessia A Ricci, Lital Adler, Rami Khoury, Giuseppe Longobardi, Rachel Slutsky, Alicia I Leikin-Frenkel, Shai Ovadia, Katharina Lange, Alessandra Rustighi, Silvano Piazza, Andrea Sacconi, Rayna Y Magesh, Faith N Keller, Jean Berthelet, Alexander Schäffer, Ron Saad, Sahar Israeli Dangoor, Karolina Szczepanowska, Iris Barshack, Yang Liao, Sergey Malitsky, Alexander Brandis, Thomas Broggini, Marcus Czabanka, Wei Shi, Delphine Merino, Emma V Watson, Giovanni Blandino, Ayelet Erez, Ruth Ashery-Padan, Hind Medyouf, Luca Bertero, Giannino Del Sal, Ronit Satchi-Fainaro, Uri Ben-David.

Brain metastasis (BM) carries a poor prognosis, yet the molecular basis of brain tropism remains unclear. Analysis of breast cancer BM (BCBM) revealed pervasive p53 inactivation through mutations and/or aneuploidy, with pathway disruption already present in primary tumors. Functionally, p53 inactivation markedly increased BCBM formation and growth in vivo, causally linking p53 perturbation to BM. Mechanistically, p53 inactivation upregulated SCD1 and fatty acid synthesis (FAS), essential for brain-metastasizing cells; SCD1 knockout abolished the p53-dependent growth advantage. Molecularly, p53 suppressed SCD1 directly through promoter binding and indirectly by downregulating its co-activator DEPDC1. Astrocytes further enhanced FAS by secreting factors that were metabolized in a p53-dependent manner, promoting tumor survival, proliferation and migration. Finally, p53-deficient tumors were sensitive to FAS inhibition ex vivo and in vivo. Thus, we identify p53 inactivation as a driver of BCBM, reveal p53-dependent and astrocyte-dependent FAS modulation and highlight FAS as a therapeutically targetable BCBM vulnerability.

DOI: https://doi.org/10.1038/s41588-025-02446-1