bims-tremyl 2025-09-21 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–09–21
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.
Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.
Multi-dimensional analysis of adult acute myeloid leukemia cross-continents reveals age-associated trends in mutational landscape and treatment outcomes (Acute Myeloid Leukemia Cooperative Group & Alliance for Clinical Trials in Oncology).
Granulocyte abundance and maturation state at diagnosis predicts treatment-free remission in CML.
FLAG-IDA plus venetoclax for children, adolescents, and young adults with newly diagnosed AML.
A genome-wide screen identifies Runx2 as a novel regulator of hematopoietic stem cell expansion and T-cell commitment.
Intensive chemotherapy vs venetoclax/hypomethylating agents for patients aged 60 to 75 years with favorable, NPM1-mutated AML.
Clonal Hematopoiesis Dynamics and Evolutionary Fitness During Cancer Treatment Impact Clinical Outcomes.
The watch-and-wait approach for patients with juvenile myelomonocytic leukemia: results of the French cohort.
Bone Marrow Adipokine Mediates Hematopoietic Regeneration and Stem Cell Fitness.
Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.
CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness.
Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution.
Epitranscriptomic advances in normal and malignant hematopoiesis.
VEXAS syndrome anemia is a mosaic erythroblastopenia.
Can we move beyond myeloablative conditioning (MAC)? A comparison of MAC versus reduced intensity conditioning (RIC) in patients aged younger than 65 years undergoing allogeneic haematopoietic cell transplantation using ATG-PTCy-CSA for GVHD prophylaxis.
Pre-Hematopoietic Cell Transplant Ruxolitinib in Transplant-Eligible Patients with Myelofibrosis: Long-Term Outcomes of a Phase II Prospective Study.
OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.
Thiotepa-busulfan-fludarabine compared to clofarabine-based conditioning for haploidentical transplant with posttransplant cyclophosphamide in patients with myeloid malignancies: a retrospective study from the SFGM-TC.
A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.
METTL16-mediated inhibition of MXD4 promotes leukemia through activation of the MYC-MAX axis.
Understanding and imaging PHGDH-driven intrinsic resistance to mutant IDH inhibition in gliomas.
Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia.
The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis.
Covariation MS uncovers a protein that controls cysteine catabolism.
Primary Results From Blood and Marrow Transplant Clinical Trials Network 1702: Clinical Transplant-Related Long-Term Outcomes of Alternative Donor Allogeneic Transplantation.
JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.
Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
A novel PML germline variant as a candidate predisposing genetic aberration in familial acute myeloid leukaemia.
Monocyte-endothelial interactions as a targetable node in clonal hematopoiesis-mediated cardiovascular disease.
Statins Enhance the Efficacy of Pegylated Interferon-α2 in Philadelphia-Negative Chronic Myeloproliferative Neoplasms.
Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody.
ELOVL6 activity attenuation induces mutant KRAS degradation.
An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.

Exp Hematol. 2025 Sep 17. pii: S0301-472X(25)00541-7. [Epub ahead of print] 105252

A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.

Pawan Bhat, Joseph C Van Amburg, Chad R Potts, Thomas J Gracie, Justin A Cartailler, Alyssa C Parker, Michael R Savona, Rui Lu, Stanley C Lee, Robert S Welner, Alexander G Bick, P Brent Ferrell Jr.

  Myelodysplastic syndromes (MDS) are a group of malignant clonal disorders that are characterized by functional impairment of hematopoiesis, morphologic dysplasia, and genetic heterogeneity1. While less likely to transform to acute leukemia, lower-risk MDS (LR-MDS) include patients with IPSS-M moderate low risk, low risk, and very low risk patients2 and have a limited median survival of 3 to 10 years3. Further, there is growing interest in discovering translational targets of LR-MDS pathophysiology. Clonal populations within the hematopoietic stem and progenitor (HSPC) to myeloid differentiation spectrum are widely considered to be a major contributor to MDS pathophysiology4. A granular assessment of cell-type and lineage-specific states that contribute to LR-MDS pathophysiology remains to be elucidated. Here, we leverage single-cell transcriptomics to characterize cell states across the HSPC-myeloid differentiation landscape in LR-MDS. We develop a 30-gene score to classify LR-MDS HSPCs and identify novel molecular features of LR-MDS. The genes in our score suggest dysfunction in vesicular trafficking, which we further resolve across the myeloid differentiation axis. The gene products of vesicular trafficking-related pathways may be suitable translational targets for LR-MDS. TEASER ABSTRACT: We leveraged single-cell transcriptomics to differentiate low-risk MDS and healthy cells from patient bone marrow samples. A combination approach of network analysis and classification was used to identify a 30-gene signature that distinguishes MDS HSPCs from HD HSPCs. Upregulation of pathways related to protein translation, pro-inflammatory cytokine production, and vesicular trafficking were observed. Lastly, we stratify the thirty genes by their expression across the HSPC-myeloid differentiation axis and highlight divergent expression patterns in genes related to vesicular trafficking components.

Keywords:  HSPC; Single-cell; cell states; classifier; machine learning; myelodysplastic syndromes; myeloid; myeloid differentiation; systems biology; transcriptomics; translational medicine; vesicular trafficking

DOI:  https://doi.org/10.1016/j.exphem.2025.105252
Leukemia. 2025 Sep 19.

Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.

Paolo Mazzeo, Sarah Mae Penir, Evgenii Shumilov, Sebastian Wolf, Björn Häupl, Katharina Markus, Katayoon Shirneshan, Katharina Rittscher, Elzbieta Brzuszkiewicz, Enver Aydilek, Hannes Treiber, Thomas Oellerich, Christina Ganster, Detlef Haase, Raphael Koch.

Treatment of high-risk Myelodysplastic Neoplasms (hr-MDS) and (secondary) Acute Myeloid Leukemia (AML) remains a clinical challenge. The combination of azacitidine and venetoclax (aza/ven) may improve treatment outcomes, but still fails in a significant fraction of patients. We established a single-center collection of longitudinal samples from patients with MDS and AML/sAML and performed comprehensive genetic, proteomic and functional apoptosis profiling to identify biomarkers and targetable escape mechanisms to aza/ven. Baseline genetic characterization (n = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] timepoints) revealed distinct genetic profiles of clonal evolution. Functional BH3-profiling at treatment initiation identified heterogeneous dependencies on BCL-2 family members. Notably, high BCL-2 dependence correlated with genetic response to aza/ven and improved overall survival, whereas increased BCL-xL dependence was associated with resistance. We further identified patterns of acquired resistance, with loss of apoptotic priming and shifts in anti-apoptotic dependencies contributing to treatment failure. BH3 profiling revealed functional shifts toward MCL-1 and/or BCL-xL in individual cases, suggesting potential therapeutic targets to overcome resistance. In vitro, BCL-xL inhibition effectively counteracted resistance in increased BCL-xL dependence cases. In summary, we characterized treatment-associated clonal evolution in MDS and AML, providing insights into clinical response, disease progression and potential individualized therapeutic strategies.

DOI: https://doi.org/10.1038/s41375-025-02756-7
Leukemia. 2025 Sep 19.

Multi-dimensional analysis of adult acute myeloid leukemia cross-continents reveals age-associated trends in mutational landscape and treatment outcomes (Acute Myeloid Leukemia Cooperative Group & Alliance for Clinical Trials in Oncology).

Monica Cusan, Karilyn Larkin, Deedra Nicolet, Vindi Jurinovic, Krzysztof Mrózek, Aarif M N Batcha, Maja Rothenberg-Thurley, Stephanie Schneider, Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E Berdel, Bernhard J Woermann, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Philipp A Greif, James S Blachly, Alice S Mims, Christopher J Walker, Michael C Walker, Christopher C Oakes, Shelley Orwick, Andrew J Carroll, William G Blum, Bayard L Powell, Jonathan E Kolitz, Joseph O Moore, Robert J Mayer, Richard A Larson, Richard M Stone, John C Byrd, Klaus H Metzeler, Tobias Herold, Ann-Kathrin Eisfeld.

The outcome of patients with acute myeloid leukemia (AML) worsens with increasing age. Dichotomization into "younger" and "older" patients is clinically routine and often dictates treatment options. We aimed to delineate whether molecular genetic features and/or outcome measures support assorting patient populations by age, including division into "younger" and "older" groups. We analyzed 2823 adult AML patients enrolled onto frontline chemotherapy-based clinical protocols of two cooperative study groups from USA and Germany who were profiled molecularly via targeted sequencing platforms. Frequencies of gene mutations and cytogenetic findings were depicted in 5-year age increments. Clinical outcomes of 2756 AML patients were analyzed with respect to molecular features, genetic-risk groups and age. Age-associated distributions of gene mutations and cytogenetic abnormalities were similar in both cohorts. There was almost linear shortening of overall survival with increasing age among all patients (P < 0.001) and within 2022 European LeukemiaNet-defined genetic-risk groups, with survival decreasing as age increased (favorable-risk, P < 0.001; intermediate-risk, P < 0.001; adverse-risk, P < 0.001). Although mutational profiles and outcomes of the youngest patients differed from those of older patients, there was no age cut-off identifying "younger" and "older" patients. These findings support more age-associated flexibility for drug approval and trial eligibility.

DOI: https://doi.org/10.1038/s41375-025-02644-0
Leukemia. 2025 Sep 16.

Granulocyte abundance and maturation state at diagnosis predicts treatment-free remission in CML.

Mikko Purhonen, Mikael Tatun, Katariina Luukkainen, Kevin Hung, Henri Sundquist, Oda Tafjord, Stina Söderlund, Shady Adnan-Awad, Anni Dohlen, Johanna Heikkinen, Perttu Koskenvesa, Sanna Siitonen, Satu Mustjoki, Naranie Shanmuganathan, Coral Bryce, Signe Danielsson, Henrik Hjorth-Hansen, Ulla Olsson-Strömberg, Takashi Kumagai, Shinya Kimura, David M Ross, Oscar Brück.

Treatment-free remission (TFR) has become a therapeutic objective for selected chronic-phase chronic myeloid leukemia (CP CML). However, no standardized biomarker is yet in clinical use. In this multi-center study, we explored the potential of bone marrow (BM) cytomorphology given its global accessibility and integral role in clinical diagnostics. We included diagnostic BM aspirate samples of 113 CP CML patients from seven clinical sites having attempted first TKI discontinuation. We digitized cytomorphological slides into 100x-magnified high-resolution images and analyzed these with deep learning-based image analysis. We profiled the BM cytomorphological fingerprint of CP CML patients and recapitulated the known granulocytic predominance and reduction of lymphoid, monocytic and erythroid cells in comparison to an extensive cohort of 942 control BM samples. We discovered neutrophil abundance and granulocytic maturation to associate with sustained TFR. We confirmed these visually and demonstrated their independent impact over known clinical factors. Our study underlines the potential of computational BM cytomorphology to identify novel clinical biomarkers and suggests that granulocytic expansion and maturation at diagnosis could reflect intrinsic disease pathology influencing TFR maintenance.

DOI: https://doi.org/10.1038/s41375-025-02769-2
Blood. 2025 Sep 19. pii: blood.2025029391. [Epub ahead of print]

FLAG-IDA plus venetoclax for children, adolescents, and young adults with newly diagnosed AML.

Reeja Raj, Samanta Catueno, Amber Gibson, David McCall, Miriam B Garcia, Cesar Nunez, Michael E Roth, Koji Sasaki, Priti Tewari, Ghayas C Issa, Aziz Farhat, Jeremy S Connors, Irtiza Naseer Sheikh, Yuki Nishida, Joanna S Yi, Alexandra M Stevens, Alex Bataller, Kapil N Bhalla, Demetrios Petropoulos, Naval G Daver, Tapan M Kadia, Branko Cuglievan, Courtney D DiNardo.

FLAG-IDA with venetoclax shows promise as frontline therapy for pediatric AML. In 12 patients treated at MD Anderson, most achieved remission with good early survival outcomes and many proceeded to transplant. Common toxicities included cytopenias comparable to previous regimens.

DOI: https://doi.org/10.1182/blood.2025029391
Blood. 2025 Sep 17. pii: blood.2025029115. [Epub ahead of print]

A genome-wide screen identifies Runx2 as a novel regulator of hematopoietic stem cell expansion and T-cell commitment.

Grace A Meaker, Matthew Nicholls, Catherine Chahrour, Ian Hsu, Alastair Smith, Yavor Bozhilov, Maurice Ga Hay Leung, Hugo Vassort, Leonid Olender, Oliver Beaven, Xinran Huang, Elizabeth J Brown, Marlies Vanden Bempt, Hwei Minn Khoo, Joydeep Bhadury, Thomas A Milne, Adam C Wilkinson.

Self-renewing multipotent hematopoietic stem cells (HSCs) are a rare but important cell population which can reconstitute the entire blood and immune system following transplantation. Due to their rarity, it has been difficult to comprehensively study the mechanisms regulating HSC activity. However, recent improvements in hematopoietic stem and progenitor cell (HSPC) culture methods using polyvinyl alcohol-based media now facilitate large-scale ex vivo HSC expansion. Here we performed a genome-wide CRISPR knockout (KO) screen in primary mouse HSPCs to discover novel regulators of ex vivo expansion. The screen identified Runx2 as a strong negative regulator of HSC expansion, which we validated using ex vivo and in vivo assays. Loss of Runx2 increased the frequency of immunophenotypic HSCs in HSPC cultures by ~3-fold. Following expansion, these Runx2-KO HSCs engrafted at ~5-fold higher levels in transplantation assays. Non-cultured Runx2-KO HSCs also displayed enhanced reconstitution potential, but loss of Runx2 did not alter blood parameters. Notably however, T-cell reconstitution was diminished from Runx2-KO HSCs, and we further validated an additional role for Runx2 in T-cell commitment using ex vivo and in vivo assays. In summary, we have identified a multifaceted role for Runx2 in HSCs, as a negative regulator of HSC self-renewal and as a facilitator of T-cell commitment. These results will contribute understanding transcriptional regulation of hematopoiesis and improve HSC therapies.

DOI: https://doi.org/10.1182/blood.2025029115
Blood Neoplasia. 2025 Nov;2(4): 100133

Intensive chemotherapy vs venetoclax/hypomethylating agents for patients aged 60 to 75 years with favorable, NPM1-mutated AML.

Andrew D Zale, Venkata Preetam Sandeep Kaduluri, Jonathan A Webster, Mark J Levis, Ivana Gojo, Amy E DeZern, Gabriel Ghiaur, Lukasz P Gondek, William Brian Dalton, Theodoros Karantanos, Tania Jain, Gabrielle T Prince, Richard J Jones, B Douglas Smith, Alexander J Ambinder.

Patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) without a FLT3-internal tandem duplication mutation are considered to have favorable-risk disease that may be cured with intensive chemotherapy (7+3; IC) alone. As patients age, the potential for cure without transplant is counterbalanced by morbidity associated with IC. Venetoclax combined with a hypomethylating agent (VEN/HMA) is approved for patients aged ≥75 years or those ineligible for IC, and the regimen is therefore frequently utilized in patients between 60 and 75 years of age. The differences in outcomes between patients with NPM1-mutated, favorable-risk AML who receive IC and VEN/HMA are unknown. We performed a retrospective analysis of patients aged 60 to 75 years with favorable risk, NPM1-mutated AML and compared overall survival (OS) between those treated with IC vs VEN/HMA. We identified 55 patients who met eligibility criteria. Thirty-six patients (65%) received first-line IC, and 19 patients (35%) received first-line VEN/HMA. There was no statistical difference in OS between groups (median survival: IC, 6.2 years; 95% CI, 3.26 years-NR, and VEN/HMA, 4.9 years; 95% CI, 1.1 years-NR). Sixty-day survival in the IC and VEN/HMA cohorts were 97.2% and 100%, respectively. In a univariate analysis, allogeneic hematopoietic cell transplant (alloHCT) in first remission was associated with improved OS (hazard ratio, 0.30; 95% CI, 0.12-0.74), although there were no differences when induction therapy was stratified by alloHCT status. These data suggest that outcomes for patients aged 60 to 75 years with NPM1-mutated AML are comparable between patients initially treated with IC or VEN/HMA.

DOI: https://doi.org/10.1016/j.bneo.2025.100133
medRxiv. 2025 Sep 02. pii: 2025.08.27.25334581. [Epub ahead of print]

Clonal Hematopoiesis Dynamics and Evolutionary Fitness During Cancer Treatment Impact Clinical Outcomes.

Mona Arabzadeh, Yi-Han Tang, Christelle Colin-Leitzinger, Sadegh Marzban, Daniel Walgenbach, Stefania Morganti, Vaidhyanathan Mahaganapathy, Erika Harper, Mingxiang Teng, Jacob K Kresovich, Iman Washington, Heather A Parsons, Judy E Garber, Jeffrey West, Shridar Ganesan, Hossein Khiabanian, Nancy Gillis.

Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without other hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of breast cancer patients and showed that cytotoxic treatments (chemotherapy ± radiation) led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. CH clones that were positively selected and expanded through dose-dependent therapeutic bottlenecks frequently harbored mutations in TP53, PPM1D, SRCAP, DNMT3A, and YLPM1. Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared to patients with unchanging or negatively selected CH across all therapies. These findings, corroborated in independent breast cancer and pan-cancer cohorts, provide strong evidence for clinical relevance of changes in CH during cancer treatment which may help identify patients at high risk for inferior outcomes.

DOI: https://doi.org/10.1101/2025.08.27.25334581
Blood. 2025 Sep 19. pii: blood.2025029916. [Epub ahead of print]

The watch-and-wait approach for patients with juvenile myelomonocytic leukemia: results of the French cohort.

Quentin Neven, Chloé Arfeuille, Aurélie Caye-Eude, Pauline Durand, Elodie Lainey, Odile Fenneteau, Brigitte Nelken, Marie Nolla, Arthur Sterin, Audrey Grain, Céline Khouri, Mathieu Simonin, Marie-Emilie Dourthe, Mony Fahd, Fréderic Millot, Bénédicte Neven, Arnaud Petit, Sylvie Chevret, Jean-Hugues Dalle, André Baruchel, Hélène Cavé, Marion Strullu.

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric myeloproliferative neoplasm for which hematopoietic stem cell transplantation (HSCT) is currently the only established curative therapy. However, a watch-and-wait (W&W) approach has shown promise for long-term survival in selected cases. In this real-world study, we analyzed outcomes of JMML patients initially managed with a W&W strategy within a nationwide cohort of 161 genetically characterized cases. W&W was chosen for 35 patients, with increasing adoption over time, reaching 39% in the 2016-2021 period. Most patients carried mutations in CBL (43%), NRAS (34%), or homozygous germline SH2B3 (14%). Over a median follow-up of 6.5 years, 86% (30/35) achieved long-term survival with partial or complete resolution of myeloproliferative symptoms, although clonal hematopoiesis persisted in nearly all survivors (28/30). Disease progression occurred in five patients (CBL: n=3, NRAS: n=1, PTPN11: n=1), mostly within two years post-diagnosis. Overall, in the W&W cohort, the 5-year OS and EFS were 93.1% and 84.5%. In NRAS-mutated cases, age <30 months, normal to slightly elevated fetal hemoglobin, platelet >45x109/L, the absence of additional somatic mutations and low DNA methylation profile were associated with favorable outcomes. In CBL-driven JMML, no predictive factor of adverse evolution was identified. Notably, W&W was effective in all patients with homozygous germline SH2B3, regardless of clinical or biological presentation. These findings support W&W as a viable alternative in up to 30% of JMML patients, potentially sparing them from HSCT-associated risks. Given the persistence of clonal hematopoiesis and the risk of extra-hematological complications, long-term monitoring remains essential.

DOI: https://doi.org/10.1182/blood.2025029916
bioRxiv. 2025 Sep 02. pii: 2025.08.28.672647. [Epub ahead of print]

Bone Marrow Adipokine Mediates Hematopoietic Regeneration and Stem Cell Fitness.

Parash Prasad, Angelo D'Alessandro, Abhishek K Singh, Yi Zheng, John Manis, Li Chai, Mohd Kamran, Mark Soliman, Ashley M Wellendorf, Leo Mejia, Hongbo R Luo, Sean R Stowell, Shin-Young Park, Martin J Aryee, Mercedes Ricote, Nathan Salomonis, Jose A Cancelas.

Bone marrow (BM) hematopoietic stem cells (HSCs) are exquisitely sensitive to cues from the BM microenvironment (ME), which is critical for their engraftment and regeneration following myeloablative stress. Retinoic acid signaling, acting on both HSCs and niche cells, has emerged as a central regulator of this process. Among ME components, BM adipocytes (BMAs), which can comprise up to 45% of BM volume and expand dramatically during the pancytopenic phase after myeloablation, play a previously underappreciated role in hematopoietic recovery. Here, we identify retinoid X receptor (RXR) signaling in BMAs as a key regulator of the adipokine Resistin, which promotes HSC self-renewal and functional fitness by activating NF-κB signaling. Conditional loss of RXR in adiponectin-expressing cells suppressed Resistin production, resulting in reduced NF-κB activity in HSCs, impaired self-renewal, and defective multilineage hematopoietic regeneration. Functionally, in vivo Resistin neutralization impaired hematopoietic reconstitution, whereas supplementation with either monomeric or dimeric Resistin enhanced HSC self-renewal and long-term lympho-hematopoietic reconstitution in an NF-κB-dependent manner. Together, these findings establish BMA-derived Resistin as an RXR-dependent, critical extrinsic regulator of HSC self-renewal and regenerative hematopoiesis, underscoring its essential role in lympho-myeloid reconstitution after myeloablation. Disclosures : The authors declare no relevant conflicts of interest.

DOI: https://doi.org/10.1101/2025.08.28.672647
Mol Oncol. 2025 Sep 16.

Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.

Shuangshuang Wu, Jianlei Zhao, Aaban Asfar Azmi, Avanti Gupte, Jenna Thibodeau, Shuang Liu, Jinli Yang, Guan Wang, Holly Edwards, Lisa A Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Julie Boerner, Maik Hüttemann, Jay Yang, Yue Wang, Jeffrey W Taub, Yubin Ge.

  Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.

Keywords:  AZD4573; acute myeloid leukemia; azacitidine; venetoclax

DOI:  https://doi.org/10.1002/1878-0261.70124
Leukemia. 2025 Sep 15.

CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness.

Damia Romero-Moya, Eric Torralba-Sales, Cristina Calvo, Oskar Marin-Bejar, Maria Magallon-Mosella, Maximiliano Distefano, Joan Pera, Julio Castaño, Francesca De Giorgio, Jessica Gonzalez, Arnau Iglesias, Clara Berenguer-Balaguer, Marcel Schilling, Mireya Plass, Lorenzo Pasquali, Albert Català, Oscar Molina, Marcin W Wlodarski, Anna Bigas, Alessandra Giorgetti.

GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34+ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.

DOI: https://doi.org/10.1038/s41375-025-02771-8
Leukemia. 2025 Sep 15.

Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution.

E Onur Karakaslar, Eva M Argiro, Nadine E Struckman, Ramin Shirali Hz, Jeppe F Severens, M Willy Honders, Susan L Kloet, Hendrik Veelken, Marcel Jt Reinders, Marieke Griffioen, Erik B van den Akker.

NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas of NPM1-mutated AML, collectively reconstituting complete myelopoiesis. The three NPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, leukemic cells were detected across different myeloid cell clusters, indicating that NPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the three NPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing in NPM1-mutated AML that may have potential relevance for prognosis and treatment of patients with NPM1-mutated AML.

DOI: https://doi.org/10.1038/s41375-025-02745-w
Leukemia. 2025 Sep 19.

Epitranscriptomic advances in normal and malignant hematopoiesis.

Maria Eleftheriou, James Russell, Konstantinos Tzelepis.

RNA modifications, collectively termed the epitranscriptome, constitute a dynamic layer of post-transcriptional regulation that governs RNA splicing, stability, localization, translation, and decay. In the hematopoietic system, these chemical marks influence stem cell fate, lineage specification, immune surveillance, and malignant transformation through context-dependent regulation of mRNA, tRNA, rRNA, and non-coding RNAs. Here, we focus on RNA modifications and editing events with emerging mechanistic and translational relevance in normal and malignant hematopoiesis, highlighting those implicated in stem cell dynamics, leukemic progression, and therapeutic resistance. Specifically, we discuss N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C), pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, and RNA glycosylation. Particular attention is given to enzymes such as METTL3, METTL1, ADAR1, and NAT10, whose dysregulation sustains leukemic stem cell programmes, promotes immune evasion, and confers treatment resistance. With the first-in-class METTL3 inhibitor STC-15 now in early-phase clinical trials in solid tumours (NCT05584111, NCT06975293), and additional RNA-modifying enzyme inhibitors advancing preclinically, these pathways are emerging as therapeutically tractable, including in hematological cancers. Furthermore, integrating epitranscriptomic profiles into genomic risk frameworks may also improve disease stratification, minimal residual disease (MRD) monitoring, and the identification of targetable vulnerabilities. Together, these insights position RNA modifications as central to blood cancer biology and support their integration into next-generation diagnostic, prognostic, and therapeutic strategies.

DOI: https://doi.org/10.1038/s41375-025-02765-6
Blood. 2025 Sep 19. pii: blood.2025029081. [Epub ahead of print]

VEXAS syndrome anemia is a mosaic erythroblastopenia.

Francois Rodrigues, Giulia Hardouin, Sara El Hoss, Aya Ghoul, Emilie-Fleur Gautier, Michaël Dussiot, Maria A Lizarralde-Iragorri, Annalisa Santini, Sandy Peltier, Pascal Amireault, Vanessa Soldan, Annarita Miccio, Mounia Debili, Vincent Jachiet, Thiago Trovati Maciel, Julien Rossignol, Eric Allemand, Arsène M Mékinian, Sophie Anne Georgin-Lavialle, Mohammad Salma, Eric Soler, Pierre-Emmanuel Gleizes, Marie-Francoise O'Donohue, Olivier Kosmider, Manuel S Rodriguez, Olivier Hermine.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.

DOI: https://doi.org/10.1182/blood.2025029081
Br J Haematol. 2025 Sep 18.

Can we move beyond myeloablative conditioning (MAC)? A comparison of MAC versus reduced intensity conditioning (RIC) in patients aged younger than 65 years undergoing allogeneic haematopoietic cell transplantation using ATG-PTCy-CSA for GVHD prophylaxis.

Ruah Alyamany, Ahmed Alnughmush, Mats Remberger, Arjun Datt Law, Wilson Lam, Dennis Dong Hwan Kim, Fotios V Michelis, Ivan Pasic, Igor Novitzky-Basso, Armin Gerbitz, Rajat Kumar, Jonas Mattsson, Auro Viswabandya.

  Allogeneic haematopoietic cell transplantation (HCT) offers a curative option for numerous haematological disorders; however, its myeloablative conditioning (MAC) regimens are associated with substantial toxicity. Reduced intensity conditioning (RIC) regimens were developed to mitigate transplant-related toxicity and broaden eligibility-particularly for older or medically unfit patients-though their use in younger, fit patients remains debated. In this retrospective study, we compared outcomes between MAC and RIC in patients aged younger than 65 years undergoing allogeneic HCT with a unified graft-versus-host disease (GVHD) prophylaxis regimen comprising anti-thymocyte globulin (ATG), post-transplant cyclophosphamide (PTCy) and ciclosporin (CsA). Propensity score matching was applied to reduce confounding. At 2 years post-transplant, there were no statistically significant differences in overall survival (OS) between the groups (MAC: 68.6% vs. RIC: 65.9%; p = 0.61) or in non-relapse mortality (NRM) (MAC: 15.8% vs. RIC: 12.5%; p = 0.26). However, relapse incidence was significantly higher in the RIC group (27.0%) than in the MAC group (16.1%; p = 0.01). These findings reinforce the continued relevance of MAC in younger patients who are candidates for intensive therapy, as it appears to offer superior disease control without a concomitant increase in NRM. Prospective studies are warranted to further delineate the role of conditioning intensity in the context of contemporary GVHD prophylaxis.

Keywords:  GVHD prophylaxis; conditioning; myeloablative; reduced intensity; stem cell transplant

DOI:  https://doi.org/10.1111/bjh.70170
Transplant Cell Ther. 2025 Sep 13. pii: S2666-6367(25)01446-0. [Epub ahead of print]

Pre-Hematopoietic Cell Transplant Ruxolitinib in Transplant-Eligible Patients with Myelofibrosis: Long-Term Outcomes of a Phase II Prospective Study.

Rachel B Salit, Xinyi Fan, Ted A Gooley, Anna B Halpern, Nellie Ratsamee, Anise Marshall, Bart L Scott, H Joachim Deeg.

BACKGROUND: Ruxolitinib (Rux), the first FDA-approved JAK-inhibitor for the treatment of myelofibrosis (MF), was initially studied in patients who were ineligible for hematopoietic cell transplantation (HCT). However, the resultant decrease in splenomegaly and improvement in symptoms allowed some of the study patients to become HCT eligible. We aimed to determine if giving Rux to HCT-eligible MF patients would yield favorable HCT outcomes in relation to a historical cohort at our center.
METHODS: We conducted a single-arm Phase II prospective single-center study of Rux followed by HCT in adult patients with primary and secondary MF between 2014 - 2020. Patients were not required to have symptoms or splenomegaly. Patients took Rux for at least 8 weeks (no maximum) prior to start of conditioning and tapered off by Day - 4 of HCT conditioning.
RESULTS: 101 patients were enrolled on study of which 61 (60%) proceeded to HCT (59% primary MF, 70% DIPSS intermediate-2 or high-risk), median age 57 years (range 34 -71) after a median of 7 months (range: 2-89) on Rux. Patients engrafted at a median of 20 days; there was one primary graft failure. Non-relapse mortality (NRM) was 13% at 1-year compared to 26% in our historical cohort. With a median follow-up of 5.6 years among survivors, overall survival (OS) was 79% (95% CI 69-90) at 2 years compared to 67% in our historical cohort; 5- year survival was 74% (95%CI 64-86). The hazard ratio (HR) of death for those who had a Rux response relative to those who did not was HR = 0.57 (95% CI, 0.20-1.61, p = 0.29).
CONCLUSION: In a prospective Phase II study, patients receiving pre-HCT Rux had encouraging NRM and survival rates relative to historical patients at our center who proceeded to HCT without prior Rux.

DOI: https://doi.org/10.1016/j.jtct.2025.09.020
Cell Metab. 2025 Sep 16. pii: S1550-4131(25)00381-X. [Epub ahead of print]

OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.

Christina Mayerhofer, Dan Li, Trine Kristiansen, Ernst Mayerhofer, Azeem Sharda, Giulia Schiroli, Karin Gustafsson, Lingli He, Michael Mazzola, Sam Keyes, Anna Kiem, Eve Crompton, Yanxin Xu, Sovannarith Korm, Zhixun Dou, Charles Vidoudez, Peter G Miller, Nick van Gastel, Timothy A Graubert, David T Scadden.

  Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.

Keywords:  BCAA; OGFOD1; Ribo-seq; acute myeloid leukemia; chemoresistance; metabolism; protein biosynthesis; ribosome pausing; translation accuracy

DOI:  https://doi.org/10.1016/j.cmet.2025.08.008
Bone Marrow Transplant. 2025 Sep 15.

Thiotepa-busulfan-fludarabine compared to clofarabine-based conditioning for haploidentical transplant with posttransplant cyclophosphamide in patients with myeloid malignancies: a retrospective study from the SFGM-TC.

Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

The optimal reduced-intensity conditioning (RIC) regimen for haploidentical hematopoietic stem cells transplantation (haplo-HSCT) using post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis has yet to be determined. Potential RIC regimen for haplo-HSCT in myeloid malignancies include Clofarabine-Baltimore (CloB) and TBF (thiotepa-busulfan-fludarabine). This multicenter retrospective study compared 297 adult patients receiving CloB (n = 59) or TBF (n = 238). The main diagnoses were acute myeloid leukemia (63%), 36% having adverse risk features. Median follow-up was 22.7 months. No significant differences were observed in overall (OS), progression-free (PFS), or GVHD-free relapse-free survival. However, 2-year non-relapse mortality (NRM) was higher after TBF (34% vs 21%, HR: 0.38; 95%CI: 0.20-0.75, p = 0.005), although the relapse incidence was lower (13% vs 23%, HR: 1.94; 95%CI: 0.98-3.87, p = 0.059). A 1:1 propensity score matching allowed the comparison of 53 CloB with 53 TBF. CloB was associated with improved 2-year OS (63% vs 44%, p = 0.02) due to a higher 2-year NRM in the TBF group (48% vs 19%, p = 0.002). By multivariate analysis, CloB remained associated with better OS (HR 0.52, 95% I 0.28-0.99, p = 0.045) and TBF with higher NRM (HR 3.43, 95%CI 1.59-7.41, p = 0.002). These results suggest that CloB is superior to TBF as a RIC regimen prior to haplo-HSCT.

DOI: https://doi.org/10.1038/s41409-025-02709-9
bioRxiv. 2025 Sep 10. pii: 2025.09.09.675200. [Epub ahead of print]

A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.

Paige A Barta, Leopold Garnar-Wortzel, Timothy R Bishop, Rachel E Hayward, Lauren M Hargis, James B Shaum, Hui Si Kwok, Brian B Liau, Benjamin F Cravatt, Michael A Erb.

Transcriptional regulatory proteins are frequent drivers of oncogenesis and common targets for drug discovery. The transcriptional co-activator, ENL, which is localized to chromatin through its acetyllysine-binding YEATS domain, is preferentially required for the survival and pathogenesis of acute leukemia. Small molecules that inhibit the ENL YEATS domain show anti-leukemia effects in preclinical models, which is thought to be caused by the downregulation of pro-leukemic ENL target genes. However, the transcriptional effects of ENL YEATS domain inhibitors have not been studied in models of intrinsic or acquired resistance and, therefore, the connection between proximal transcriptional effects and downstream anti-proliferative response is poorly understood. To address this, we identified models of intrinsic and acquired resistance and used them to study the effects of ENL YEATS domain inhibitors. We first discovered that ENL YEATS domain inhibition produces similar transcriptional responses in naive models of sensitive and resistant leukemia. We then performed a CRISPR/Cas9-based genetic modifier screen and identified in-frame deletions of the essential transcriptional regulator, PAF1, that confer resistance to ENL YEATS domain inhibitors. Using these drug-resistance alleles of PAF1 to construct isogenic models, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL antagonists.

DOI: https://doi.org/10.1101/2025.09.09.675200
Oncogene. 2025 Sep 14.

METTL16-mediated inhibition of MXD4 promotes leukemia through activation of the MYC-MAX axis.

Guglielmo Bove, Mehrad Babaei, Alberto Bueno-Costa, Sajid Amin, Nicla Simonelli, Rosaria Benedetti, Carmela Dell'Aversana, Mariarosaria Conte, Liliana Montella, Vincenzo Summa, Margherita Brindisi, Maria Rosaria Del Sorbo, Marco Crepaldi, Gregorio Favale, Nuria Profitos-Peleja, Vincenzo Carafa, Gaël Roué, Fortunato Ciardiello, Annalisa Capuano, Hendrik G Stunnenberg, Wouter L Megchelenbrink, Angela Nebbioso, Manel Esteller, Lucia Altucci, Nunzio Del Gaudio.

N6-methyladenosine (m6A) is an RNA modification that governs multiple aspects of RNA metabolism, including splicing, translation, stability, decay, and the processing of marked transcripts. Although accumulating evidence suggests that the m6A writer METTL16 is involved in leukemia, the molecular pathway(s) by which it contributes to leukemogenesis remain unexplored. In this study, we shed light on a novel molecular mechanism whereby METTL16 plays a role in acute myeloid leukemia (AML) progression through an m6A-dependent manner. Our investigations revealed that METTL16 is overexpressed in primary AML cells. Genetic depletion of METTL16 or its pharmacological inhibition strongly affected the proliferation of AML cells, eventually triggering apoptosis. Transcriptome-wide analysis identified mRNA of MAX Dimerization Protein 4 (MXD4), a MYC pathway regulator, as a downstream target of METTL16. Mechanistically, we showed that METTL16 controls the stability of MXD4 mRNA, resulting in a reduction in MXD4 protein levels that indirectly activates the MYC-MAX axis, essential for leukemogenesis. Strikingly, the suppression of MXD4 rescued the expression levels of MYC target genes, restoring AML cell survival. Our findings unveil a novel METTL16-MXD4 oncogenic axis crucial for AML progression, establishing small-molecule inhibition of METTL16 as a potential therapeutic approach in leukemia and providing a new strategy to target MYC activity in cancer. Molecular model of METTL16-MXD4 axis controlling AML progression by regulating MYC activity. (A) METTL16 installs m6A on MXD4 mRNA, decreasing its stability and resulting in decreased MXD4 protein levels. (B) MXD4 reduction ensures MYC-MAX complex formation, MYC target gene expression, and AML cell growth. (C) Silencing or chemical inhibition of METTL16 stabilizes MXD4 mRNA and increases its protein levels. (D) (1) Increased MXD4 proteins may counteract MYC binding with its partner MAX, thus repressing expression of MYC target genes (early event); (2) MXD4 binds to MYC regulatory regions, decreasing MYC expression (late event) and affecting AML proliferation.

DOI: https://doi.org/10.1038/s41388-025-03563-1
bioRxiv. 2025 Sep 04. pii: 2025.08.30.673205. [Epub ahead of print]

Understanding and imaging PHGDH-driven intrinsic resistance to mutant IDH inhibition in gliomas.

Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Joanna J Phillips, Jennie W Taylor, Pavithra Viswanath.

Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and extends progression-free survival in some, but not all, IDHm glioma patients. Here, using clinically relevant patient-derived IDHm models and patient tissue, we show that phosphoglycerate dehydrogenase (PHGDH) drives intrinsic resistance to vorasidenib by promiscuously converting α-KG to D-2HG and maintaining D-2HG concentration despite IDHm inhibition. Silencing PHGDH sensitizes resistant models to vorasidenib, while conversely, overexpressing PHGDH induces vorasidenib resistance in sensitive models. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'- 2 H]-α-ketoglutarate provides an early readout of response and resistance to vorasidenib that is not available by anatomical imaging in vivo. Collectively, we have identified PHGDH-driven D-2HG production as an intrinsic mechanism of resistance to vorasidenib and diethyl-[3,3'- 2 H]α-ketoglutarate as a non-invasive tracer for interrogating intrinsic resistance in IDHm gliomas.
STATEMENT OF SIGNIFICANCE: Vorasidenib, which suppresses D-2HG production, is the first precision therapy to be approved for IDHm glioma patients. We show that PHGDH-driven restoration of D-2HG production mediates intrinsic resistance to vorasidenib in IDHm gliomas. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'- 2 H]-α-ketoglutarate enables non-invasive assessment of resistance in IDHm gliomas.

DOI: https://doi.org/10.1101/2025.08.30.673205
Leukemia. 2025 Sep 15.

Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia.

Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L Lin, David A Sallman, Sebastien Anguille, William G Blum, Anne Flament, Eytan Breman, Caroline Lonez.

The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.

DOI: https://doi.org/10.1038/s41375-025-02767-4
bioRxiv. 2025 Sep 03. pii: 2025.09.01.673558. [Epub ahead of print]

The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis.

Adam Boulton, Ashish Kabra, Nicholas Achille, Emmalee R Adelman, Dimitrios G Anastasakis, Felipe Beckedorff, Pradeepkumar Cingaram, Ying Zhang, Benjamin Leach, Ramin Shiekhattar, Akihiko Yokoyama, Markus Hafner, Maria Figueroa, Nancy Zeleznik-Le, John Bushweller.

The protein MLLT3 (AF9) is a critical regulator of hematopoiesis. The N-terminal YEATS domain of MLLT3 is an epigenetic reader that binds to acetylated as well as crotonylated lysine. Using PAR-CLIP, biochemical assays, and NMR based mapping of binding, we demonstrate that the YEATS domain of MLLT3 binds to a specific stem-loop region of the noncoding RNA 7SK. 7SK is a noncoding RNA with a well-documented function in transcriptional elongation. We developed point mutations in the YEATS domain that disrupt RNA binding while having no effect on binding of acetylated histone peptides to probe the specific role of RNA binding in MLLT3 function. Our results show loss of RNA binding by MLLT3 skews hematopoietic differentiation away from the myeloid lineage and toward the lymphoid lineage and has substantial effects on gene expression, confirming the essential nature of MLLT3-RNA binding for function.

DOI: https://doi.org/10.1101/2025.09.01.673558
Nature. 2025 Sep 17.

Covariation MS uncovers a protein that controls cysteine catabolism.

Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.

The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.

DOI: https://doi.org/10.1038/s41586-025-09535-5
J Clin Oncol. 2025 Sep 18. JCO2500206

Primary Results From Blood and Marrow Transplant Clinical Trials Network 1702: Clinical Transplant-Related Long-Term Outcomes of Alternative Donor Allogeneic Transplantation.

Stephanie J Lee, Brent Logan, Mary M Horowitz, Jason G Dehn, Joseph Pidala, Michael R Grunwald, Peter Westervelt, Nosha Farhadfar, William J Hogan, Asad Bashey, Brandon Hayes-Lattin, LaQuisa Hill, Claudio Brunstein, Sally Arai, Samer A Srour, Heather Symons, Joseph Uberti, Sumithira Vasu, Iskra Pusic, Mark Juckett, Eric Leifer, Naya He, Steven Devine, Bronwen E Shaw, Stefan O Ciurea.

PURPOSE: The likelihood of finding a human leukocyte antigen (HLA)-matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood).
METHODS: This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups.
RESULTS: A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation.
CONCLUSION: Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.

DOI: https://doi.org/10.1200/JCO-25-00206
bioRxiv. 2025 Sep 04. pii: 2025.09.03.672211. [Epub ahead of print]

JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation.

Wentao Han, Hassan Bjeije, Hamza Celik, Michael Rettig, Nancy Issa, Andrew L Young, Yanan Li, Infencia Xavier Raj, Christine R Zhang, Aishwarya Krishnan, Tyler M Parsons, Samantha C Burkart, Jason Arand, Wei Yang, Jeffrey A Magee, Grant A Challen.

Hematopoietic stem cell transplantation is a common treatment for many blood disorders and can be a life-saving therapy for patients with leukemias, lymphomas and multiple myeloma. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that genetic deletion of the polycomb repressive complex 2 (PRC2) co-factor Jarid2 in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through JARID2 inhibition. In this study, we demonstrate that both constitutive and transient knockdown of JARID2 increases the number and enhances the functionality of human HSPCs both in vitro and in vivo . This phenotype was distinct from inhibition of EZH2 in UCB cells, suggesting the mechanism was independent of PRC2 co-factor activity of JARID2. Mechanistically, JARID2 knockdown promotes a quiescent, long-term self-renewal gene expression program governed by upregulating STAT1 and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs in vivo . Taken together, these findings highlight JARID2 inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population.
One Sentence Summary: Genetic inhibition of JARID2 enhances repopulating activity of human hematopoietic stem and progenitor cells in vivo via STAT1 upregulation.

DOI: https://doi.org/10.1101/2025.09.03.672211
Sci Adv. 2025 Sep 19. 11(38): eadw9095

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.

DOI: https://doi.org/10.1126/sciadv.adw9095
Br J Haematol. 2025 Sep;207(3): 1118-1121

A novel PML germline variant as a candidate predisposing genetic aberration in familial acute myeloid leukaemia.

Thierry Soussi, Snehangshu Kundu, Pauline Gerbaud, Tatjana Pandzic, Berivan Baskin, Claes Ladenvall, François Delhommeau, Tobias Sjöblom, Panagiotis Baliakas.



Keywords:  acute myeloid leukaemia; genetic analysis; molecular diagnosis; molecular genetics

DOI:  https://doi.org/10.1111/bjh.20255
medRxiv. 2025 Sep 02. pii: 2024.02.20.24303046. [Epub ahead of print]

Monocyte-endothelial interactions as a targetable node in clonal hematopoiesis-mediated cardiovascular disease.

Alyssa C Parker, J Brett Heimlich, Joseph C Van Amburg, Yash Pershad, David A Ong, Nicole A Mickels, Laventa M Obare, Ketan J Hoey, Hannah K Giannini, Ayesha Ahmad, Caitlyn Vlasschaert, Tarak N Nandi, Ravi K Madduri, Samuel S Bailin, John R Koethe, Celestine N Wanjalla, Alexander G Bick.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) increases risk of cardiovascular disease yet the molecular mechanisms driving this association remain incompletely understood. We hypothesized that aberrant monocyte-endothelial interactions contribute to CHIP-mediated cardiovascular disease.
Methods: We performed single-cell RNA sequencing on blood and peripheral vascular tissue from 4 individuals with TET2 CHIP, 6 individuals with DNMT3A CHIP, and 25 controls. We predicted interactions between monocytes and endothelial cells based on expression of ligand-receptor pairs then modeled interactions between monocytes carrying CHIP mutations with endothelial cells in vitro . We performed an in silico genomewide perturbation screen to identify genetic targets capable of mediating these interactions and then experimentally evaluated the effect of inhibiting predicted targets on monocyte-endothelial interactions in vitro .
Results: Expression of ligand-receptor pairs on monocytes and endothelial cells from patients with and without CHIP highlighted differences in signaling likelihood for 6 key ligand-receptor pairs related to transendothelial migration. Co-culture of monocytes with human aortic endothelial cells demonstrated that monocytes carrying CHIP mutations have decreased velocity compared to monocytes without CHIP mutations. The perturbation screen suggested 11 druggable genetic targets capable of rescuing TET2 CHIP monocytes. Experimental inhibition of ICAM1 in endothelial cells and inhibition of CXCR2 in monocytes significantly increased the velocity of TET2 -mutated monocytes over endothelial cells.
Conclusions: CHIP mutations alter interactions between monocytes and endothelial cells. Therapeutics targeting CXCR2 and ICAM1 may restore normal interactions between monocytes and endothelial cells among patients with TET2 CHIP.

DOI: https://doi.org/10.1101/2024.02.20.24303046
Blood Adv. 2025 Sep 18. pii: bloodadvances.2025017016. [Epub ahead of print]

Statins Enhance the Efficacy of Pegylated Interferon-α2 in Philadelphia-Negative Chronic Myeloproliferative Neoplasms.

Isabella Diana Davidsen, Morten Kranker Larsen, Lea Löffler, Vibe Skov, Lasse Kjær, Trine Alma Knudsen, Anders Lindholm Sørensen, Sarah Friis Christensen, Sabrina Cordua, Christina Schjellerup Eickhardt-Dalbøge, Marie Hvelplund Kristiansen, Christina Ellervik, Troels Wienecke, Hans Carl Hasselbalch.

Chronic inflammation may be a key driving force in the development and progression of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Statins, commonly used to lower cholesterol, also possess anti-proliferative, proapoptotic and anti-inflammatory properties, that may be beneficial in the treatment of MPN patients. This retrospective cohort study investigated whether statin use, in addition to standard cytoreductive therapy, shortens the time required to achieve hematological and molecular responses while allowing for lower cytoreductive drug dosages. A total of 129 patients were included, with 53 receiving statins from diagnosis. The study found that statin users achieved complete hematologic response (CHR) significantly faster than non-users (median time: 8 versus 18 months; HR 2.1, 95%CI 1.4-3.1, P = 0.0003). Among patients treated with pegylated interferon-alpha2 (IFN), the CHR rate was 97% in statin users versus 83% in non-users (HR 2.5, 95%CI 1.5-3.9, P = 0.0004), and a higher proportion of statin users sustained CHR throughout follow-up. Additionally, IFN-treated statin users received a significantly lower mean dose of IFN. A dose-response relationship was observed, with higher statin intensity associated with an increase of CHR. Furthermore, statin use was significantly associated with achieving a partial molecular response among IFN-treated patients (HR 2.6, 95%CI: 1.1-6.0, P = 0.029). No significant association was observed in hydroxyurea-treated patients. These findings suggest that statins may enhance the efficacy of IFN in MPN patients, while their benefit in hydroxyurea-treated patients remains unclear. Prospective studies are warranted to further explore the therapeutic potential of statins in MPNs.

DOI: https://doi.org/10.1182/bloodadvances.2025017016
Blood. 2025 Sep 17. pii: blood.2025029836. [Epub ahead of print]

Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody.

Nathan M Newton, Kriti Agrawal, Anahi V Odell, Timothy Scott Tracy, Craig Stanway Hackett, Anne B Eldrup, Michael Whitfield, Viktor Martyanov, Michael Girardi, Esen Sefik, Richard A Flavell, Ian D Odell.

Immune driven fibrotic skin diseases including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host-disease (cGvHD) cause skin stiffening that has major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that EREG, a DC3 dendritic cell-derived EGFR ligand, is elevated in the skin and lung of patients with SSc and required for maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knock-in mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma) and SclGvHD with disease biomarkers. EREG expression in the skin was elevated in all three fibrotic diseases and a driver of TNC production by myofibroblasts in all three fibrotic diseases. TNC is a pro-inflammatory extracellular glycoprotein that functions as an endogenous TLR4 ligand which induces expression of TLR4 target genes CCL2 and IL6. Examination of skin explants from patients with active SclGvHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients, and type I collagen and FN1 in 3/4 patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.

DOI: https://doi.org/10.1182/blood.2025029836
Nat Chem Biol. 2025 Sep 15.

ELOVL6 activity attenuation induces mutant KRAS degradation.

Xiyue Hu, Ranjit Singh Atwal, Sophie Xiao, Sharif U Ahmed, Zongjie Wang, Chenlin Zhao, Hansen Wang, Shana O Kelley.

KRAS is one of the most frequently mutated oncogenes in cancer. Targeting mutant KRAS directly has been challenging because of minor structural changes caused by mutations. Despite recent success in targeting KRAS-G12C, targeted therapy for another hotspot mutant, KRAS-G12V, has not been described. We used CRISPR-Cas9 genome-wide knockout screens to identify genes that specifically modulate mutant KRAS harboring the G12V substitution. Our top hit, a fatty acid elongase (ELOVL6), showed remarkable selectivity in diminishing KRAS-G12V protein expression and aberrant oncogenic signaling associated with mutant KRAS. Our studies reveal that ELOVL6 can be targeted to control the production of phospholipids exploited by KRAS mutants for function-targeted and trigger-targeted degradation of the protein. Our results demonstrate the basis for a first-in-class small-molecule inhibitor to selectively clear KRAS-G12V from cancer cells.

DOI: https://doi.org/10.1038/s41589-025-01998-x
bioRxiv. 2025 Sep 04. pii: 2025.09.01.673389. [Epub ahead of print]

An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.

Ksenia R Safina, Dylan A Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer Trowbridge, Vijay G Sankaran, Peter van Galen.

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

DOI: https://doi.org/10.1101/2025.09.01.673389