bims-tremyl 2025-01-26 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–01–26
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells.
CD44-Mediated Metabolic Rewiring is A Targetable Dependency of IDH-Mutant Leukemia.
Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution.
Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).
The Fit Older Adult with Acute Myeloid Leukemia: Clinical Challenges to Providing Evidence-Based Frontline Treatment.
IL-1R1 and IL-18 Signals Regulate Mesenchymal Stromal Cells in an Aged Murine Model of Myelodysplastic Syndromes.
TP53 Mutant Variant Allele Frequency and Cytogenetics Determine Prognostic Groups in MDS/AML for Transplantation.
Robust acute myeloid leukemia engraftment in humanized scaffolds using injectable biomaterials and intravenous xenotransplantation.
Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes.
Loss of SMAD1 in acute myeloid leukemia with KMT2A::AFF1 and KMT2A::MLLT3 fusion genes.
Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines.
GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.
Clinicopathologic and Molecular Characterization of NUP98-Rearranged Acute Leukemias.
Sodium-glucose co-transporter-2 inhibitor treatment-associated changes in hemoglobin level in anemic patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms.
Comprehensive Characterization of Overt Myelofibrosis in an Asian Cohort: Phenotype, Mutation Landscape and Discordance Among Scoring Systems.
A novel KMT2A::DCP1A fusion gene in acute myeloid leukemia.
Sex dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling.
Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy.
Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia.
Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.
Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.
Folate metabolism in myelofibrosis: a missing key?
Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome.
Impact of TP53 alteration on allogeneic hematopoietic cell transplantation outcomes for myelodysplastic syndromes.
Myeloablative conditioning in cord blood transplantation for acute myeloid leukemia patients is efficacious only until age 55.
Cryo-EM structure and regulation of human NAD kinase.
Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells.

Blood. 2025 Jan 22. pii: blood.2024025886. [Epub ahead of print]

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells.

Joana L Araújo, Elvin Wagenblast, Veronique Voisin, Jessica McLeod, Olga I Gan, Suraj Bansal, Liqing Jin, Amanda Mitchell, Blaise Gratton, Sarah Kristen Cutting, Andrea Arruda, Monica Doedens, Anthea Travas, Dennis Dong Hwan Kim, Jose-Mario Capo-Chichi, Sagi Abelson, Mark D Minden, Jean Cy Wang, Manuel A Sobrinho-Simões, Perpétua Pinto-do-Ó, Eric R Lechman, John E Dick.

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-wild type (WT) AMLs, resulted in short-term leukemic grafts of FLT3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes.

DOI: https://doi.org/10.1182/blood.2024025886
Blood. 2025 Jan 22. pii: blood.2024027207. [Epub ahead of print]

CD44-Mediated Metabolic Rewiring is A Targetable Dependency of IDH-Mutant Leukemia.

Junhua Lyu, Yuxuan Liu, Ningning Liu, Hieu Vu, Feng Cai, Hui Cao, Pranita Kaphle, Zheng Wu, Giovanni A Botten, Yuannyu Zhang, Jin Wang, Sarada Achyutuni, Xiaofei Gao, Ilaria Iacobucci, Charles G Mullighan, Stephen S Chung, Min Ni, Ralph J DeBerardinis, Jian Xu.

Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring CRISPR base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia, consistent with elevated CD44 expression in IDH-mutant AML patients. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances the elimination of IDH-mutant leukemia cells. Hence, we describe an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.

DOI: https://doi.org/10.1182/blood.2024027207
Cell Genom. 2025 Jan 16. pii: S2666-979X(24)00373-2. [Epub ahead of print] 100744

Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution.

Gladys Poon, Aditi Vedi, Mathijs Sanders, Elisa Laurenti, Peter Valk, Jamie R Blundell.

  The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.

Keywords:  acute myeloid leukemia; cancer evolution; clonal hematopoiesis; early detection; evolutionary dynamics; pre-cancer; somatic mutation

DOI:  https://doi.org/10.1016/j.xgen.2024.100744
Blood Adv. 2025 Jan 18. pii: bloodadvances.2024014900. [Epub ahead of print]

Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).

Chong Chyn Chua, Sun Loo, Chun Yew Fong, Stephen B Ting, Ing S Tiong, Shaun A Fleming, Natasha S Anstee, Adam Ivey, Michael Ashby, Tse-Chieh Teh, John Reynolds, Andrew W Roberts, Andrew H Wei.

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).

DOI: https://doi.org/10.1182/bloodadvances.2024014900
Blood. 2025 Jan 24. pii: blood.2024026004. [Epub ahead of print]

The Fit Older Adult with Acute Myeloid Leukemia: Clinical Challenges to Providing Evidence-Based Frontline Treatment.

Sameem M Abedin, Geoffrey L Uy, Laura C Michaelis.

Recent advances in acute myeloid leukemia (AML) come from studies investigating younger (age<60 years) adults or older (age≥75 years) or less fit adults. Uncertainty exists for the management of otherwise healthy adults with AML in their 60s and 70s, which also represents a significant proportion of AML cases. We discuss current considerations in older, fit adults with AML including determination of fitness, what factors beyond fitness should be assessed, and finally what challenges and innovations lie ahead to improve outcomes for these patients.

DOI: https://doi.org/10.1182/blood.2024026004
Blood. 2025 Jan 22. pii: blood.2024024818. [Epub ahead of print]

IL-1R1 and IL-18 Signals Regulate Mesenchymal Stromal Cells in an Aged Murine Model of Myelodysplastic Syndromes.

Yuko Kawano, Hiroki Kawano, Mark W LaMere, Elizabeth A LaMere, Daniel K Byun, Kathleen McGrath, James Palis, Jeevisha Bajaj, Jane L Liesveld, Yoshio Katayama, Satoshi Yamazaki, Reuben Kapur, Laura M Calvi, Tzu-Chieh Ho, Michael W Becker.

Myelodysplastic syndromes (MDS) are age-related diseases characterized by bone marrow (BM) dysfunction and an increased risk of developing acute leukemia. While there is growing evidence highlighting the crucial role of the BM microenvironment (BMME) in MDS, the specific influence of inflammation on BMME changes, as well as the potential benefits of targeting cytokines therapeutically, remain to be elucidated. We previously found interleukin-1 (IL-1) to be a driver of aging phenotypes of BMME and hematopoietic stem and progenitor cells (HSPCs). In the current study, BM samples from patients with MDS demonstrated upregulated levels of IL-1 family cytokines including IL-18. Utilizing highly purified primary BM-derived mesenchymal stromal cells (MSCs), both interleukin-1b (IL-1b) and IL-18 were found to exert direct effects on MSCs, thus influencing their ability to support HSPCs as well as erythroid progenitors. This confirms the significant involvement of both these IL-1 family cytokines in regulating the BM niche. Furthermore, targeting IL-1 receptor type I (IL-1R1) mitigated these aging phenotypes in elderly mice. We subsequently employed an age-appropriate murine model of MDS by transplanting NUP98-HOXD13 transgenic mice (NHD13Tg) cells into aged wild-type mice. Treatment with inhibitors targeting interleukin-1 receptor-associated kinase 4 (IRAK4) and NLR family pyrin domain containing 3 (NLRP3) reversed the proliferation of dysfunctional MSCs and enhanced their functionality. Additionally, IRAK4 inhibition selectively suppressed MDS clonal cells while sparing non-MDS cells in the BM. These findings suggest that targeting IL-1 signaling holds promise for MDS treatment by addressing the underlying myeloid malignancy and restoring the altered BMME via BM-MSCs.

DOI: https://doi.org/10.1182/blood.2024024818
Blood Adv. 2025 Jan 24. pii: bloodadvances.2024014499. [Epub ahead of print]

TP53 Mutant Variant Allele Frequency and Cytogenetics Determine Prognostic Groups in MDS/AML for Transplantation.

Konstantinos Lontos, Rima M Saliba, Rashmi Kanagal-Shamanna, Gonca Ozcan, Jeremy Leon Ramdial, George Liwei Chen, Tapan M Kadia, Nicholas J Short, Naval G Daver, Hagop M Kantarjian, David Marin, Partow Kebriaei, Uday R Popat, Richard E Champlin, Elizabeth J Shpall, Betul Oran.

Results following hematopoietic stem cell transplantation (HSCT) for TP53-mutated myeloid malignancies are disappointing. Several HSCT centers decline to perform HSCT for patients with TP53 mutation because of poor outcomes. In this study, we analyzed 240 patients with TP53-mutated myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that underwent HSCT. We aimed to identify the patients that benefit most from HSCT. The primary outcome was progression-free survival (PFS). Fifty-two percent of the cohort had AML and the median age of the cohort was 62. AML and MDS outcomes were similar. We identified several favorable prognostic factors for PFS including the absence of complex cytogenetics/5q deletion/7q deletion, a lower variant allele frequency (VAF), a mono-hit status and the use of a matched-related donor. Using classification and regression tree analysis, we identified VAF and cytogenetics as the two most important prognostic factors. Patients with TP53mut VAF ≥ 50% had a 2-year PFS of 3%, patients with TP53mut VAF < 50% and complex/5q/7q cytogenetics abnormalities had 2-year PFS of 22%. Patients with TP53mut VAF < 50% and without complex/5q/7q cytogenetics had 2-year PFS of 60%. This data informs clinical practice and helps patients decide whether to pursue HSCT.

DOI: https://doi.org/10.1182/bloodadvances.2024014499
Mol Oncol. 2025 Jan 22.

Robust acute myeloid leukemia engraftment in humanized scaffolds using injectable biomaterials and intravenous xenotransplantation.

Daniel Busa, Zdenka Herudkova, Jan Hyl, Jakub Vlazny, Filip Sokol, Kvetoslava Matulova, Adam Folta, Jakub Hynst, Lucy Vojtova, Leos Kren, Martin Repko, Zdenek Racil, Jiri Mayer, Martin Culen.

  Patient-derived xenografts (PDXs) can be improved by implantation of a humanized niche. Nevertheless, the overall complexity of the current protocols, as well as the use of specific biomaterials and procedures, limits the wider adoption of this approach. Here, we identify the essential minimum steps required to create the humanized scaffolds and achieve successful acute myeloid leukemia (AML) engraftment. We compared seven biomaterials, which included both published and custom-designed materials. The highest level of bone marrow niche was achieved with extracellular matrix gels and custom collagen fiber, both of which allowed for a simple non-surgical implantation. The biomaterial selection did not influence the following AML infiltration. Regarding xenotransplantation, standard intravenous administration produced the most robust engraftment, even for two out of four otherwise non-engrafting AML samples. In contrast, direct intra-scaffold xenotransplantation did not offer any advantage. In summary, we demonstrate that the combination of an injectable biomaterial for scaffold creation plus an intravenous route for AML xenotransplantation provide the most convenient and robust approach to produce AML PDX using a humanized niche.

Keywords:  AML; T‐cell; collagen; mouse model; ossicles; patient‐derived xenografts

DOI:  https://doi.org/10.1002/1878-0261.13790
Hemasphere. 2025 Jan;9(1): e70073

Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes.

MDS‐RIGHT consortium

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

DOI: https://doi.org/10.1002/hem3.70073
Front Oncol. 2024 ;14 1481713

Loss of SMAD1 in acute myeloid leukemia with KMT2A::AFF1 and KMT2A::MLLT3 fusion genes.

Lisa Dietsche, Kristin Stirm, Veronika Lysenko, Corina Schneidawind, Alexandar Tzankov, Anne Müller, Alexandre P A Theocharides.

   Introduction: KMT2A-rearrangements define a subclass of acute leukemias characterized by a distinct gene expression signature linked to the dysfunctional oncogenic fusion proteins arising from various chromosomal translocations involving the KMT2A (also known as MLL1) gene. Research on the disease pathomechanism in KMT2A-rearranged acute leukemias has mainly focused on the upregulation of the stemness-related genes of the HOX-family and their co-factor MEIS1.
Results: Here we report the KMT2A::AFF1 and KMT2A::MLLT3 fusion gene-dependent downregulation of SMAD1, a TGF-β signaling axis transcription factor. SMAD1 expression is lost in the majority of AML patient samples and cell lines containing the two fusion genes KMT2A::AFF1 and KMT2A::MLLT3 compared to non-rearranged controls. Loss of SMAD1 expression is inducible by introducing the respective two KMT2A fusion genes into hematopoietic stem and progenitor cells. The loss of SMAD1 correlated with a markedly reduced amount of H3K4me3 levels at the SMAD1 promoter in tested cells with KMT2A::AFF1 and KMT2A::MLLT3. The expression of SMAD1 in cells with KMT2A::AFF1 fusion genes impacted the growth of cells in vitro and influenced engraftment of the KMT2A::AFF1 cell line MV4-11 in vivo. In MV4-11 cells SMAD1 expression caused a downregulation of HOXA9 and MEIS1, which was reinforced by TGF-β stimulation. Moreover, in MV4-11 cells SMAD1 presence sensitized cells for TGF-β mediated G1-arrest.
Conclusion: Overall, our data contributes to the understanding of the role of TGF-β signaling in acute myeloid leukemia with KMT2A::AFF1 by showing that SMAD1 loss can influence the growth dynamics and contribute to the pathogenic expression of disease driving factors.

Keywords:  KMT2A rearrangement; KMT2A::AFF1; KMT2A::MLLT3; SMAD1; TGF-beta signaling; acute myeloid leukaemia

DOI:  https://doi.org/10.3389/fonc.2024.1481713
Clin Epigenetics. 2025 Jan 17. 17(1): 8

Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines.

Sam Humphries, Sean M Burnard, Courtney D Eggins, Simon Keely, Danielle R Bond, Heather J Lee.

   BACKGROUND: Hypomethylating agents (HMA), such as azacytidine (AZA) and decitabine (DAC), are epigenetic therapies used to treat some patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome. HMAs act in a replication-dependent manner to remove DNA methylation from the genome. However, AML cells targeted by HMA therapy are often quiescent within the bone marrow, where oxygen levels are low. In this study, we investigate the effects of hypoxia on HMA responses in AML cells.
RESULTS: AML cell lines (MOLM-13, MV-4-11, HL-60) were treated with DAC (100 nM) or AZA (500-2000 nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Hypoxia significantly reduced AML cell growth across all cell lines, with no additional effects observed upon HMA treatment. Hypoxia had no impact on the extent of DNA hypomethylation induced by DAC treatment, but limited AZA-induced loss of methylation from the genome. Transcriptional responses to HMA treatment were also altered, with HMAs failing to up-regulate antigen presentation pathways in hypoxia. In particular, cell surface expression of the MHC class II receptor, HLA-DR, was increased by DAC treatment in normoxia, but not hypoxia.
CONCLUSION: Our results suggest that HMA-induced antigen presentation may be impaired by hypoxia. This study highlights the need to consider microenvironmental factors when designing co-treatment strategies to improve HMA therapeutic efficacy.

Keywords:  Acute myeloid leukaemia; Human leukocyte antigens; Hypomethylating agents; Hypoxia

DOI:  https://doi.org/10.1186/s13148-025-01812-4
Blood. 2025 Jan 22. pii: blood.2024025761. [Epub ahead of print]

GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.

Fatemeh Alikarami, Hongbo M Xie, Simone S Riedel, Haley Goodrow, Declan Raymond Barrett, Leila Mahdavi, Alexandra Lenard, Changya Chen, Taylor Yamauchi, Etienne Danis, Zhendong Cao, Vu Le-Huy Tran, Mabel Minji Jung, Yapeng Li, Hua Huang, Junwei Shi, Kai Tan, David Trent Teachey, Emery H Bresnick, Tobias Neff, Kathrin Maria Bernt.

Stemness-associated cell states are linked to chemotherapy resistance in AML. We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intra- and inter-patient variability in GATA2 expression across AML patient samples. GATA2 expression varies by molecular subtype and has been linked to outcome. In a murine model, KMT2A-MLL3 driven AML originating from a stem cell or immature progenitor cell population have higher Gata2 expression and are more resistant to the standard AML chemotherapy agent doxorubicin. Deletion of Gata2 resulted in more robust induction of p53 following exposure to doxorubicin. ChIP-Seq, RNA-Seq and functional studies revealed that GATA2 regulates the expression of RASSF4, a modulator of the p53 inhibitor MDM2. GATA2 and RASSF4 are anti-correlated in human cell lines and AML patient cell bulk and single cell expression datasets. Knockdown of Rassf4 in Gata2 low cells resulted in doxorubicin or nutlin-3 resistance. Conversely, overexpression of Rassf4 results in sensitization of cells expressing high levels of Gata2. Finally, doxorubicin and nutlin-3 are synergistic in Gata2-high murine AML, as well as AML patient samples. We discovered a previously unappreciated role for GATA2 in dampening p53-mediated apoptosis via transcriptional regulation of RASSF4, a modulator of MDM2. This role for GATA2 directly links the expression of a stemness associated transcription factor to chemotherapy resistance.

DOI: https://doi.org/10.1182/blood.2024025761
Int J Lab Hematol. 2025 Jan 21.

Clinicopathologic and Molecular Characterization of NUP98-Rearranged Acute Leukemias.

Sujata Sajjan, Estelle E Oertling, Franklin Fuda, Jeffrey Gagan, Prasad Koduru, Rolando Garcia, Adelaide Kwon, Elisa Lin, Miguel Cantu, Kathleen Wilson, Olga K Weinberg, Mingyi Chen, Jesse Manuel Jaso, Tamra L Slone, Jamie Truscott, Julio Alvarenga Thiebaud, Stephen Chung, Yazan F Madanat, Weina Chen.

   INTRODUCTION: NUP98 rearrangements are rare in acute leukemias and portend a poor prognosis.
METHODS: This study explored clinicopathologic and molecular features of five patients with NUP98 rearranged (NUP98-r) acute leukemias, including three females and two males with a median age of 34 years.
RESULTS: NUP98 fusion partners were associated with distinctive leukemia characteristics and biology. Three patients had NUP98::NSD1-r acute myeloid leukemia (AML, all cytogenetically cryptic and with concomitant FLT3-ITD) and unfavorable prognoses (in two patients), one patient had NUP98::HOXA9-r AML with morphologic and immunophenotypic features resembling acute promyelocytic leukemia, and lastly, one patient had previously underreported NUP98::MLLT1-r B/T mixed phenotype acute leukemia. After a median follow-up of 24.7 months, median overall survival was 30 months and three of five patients (60%) remained in complete remission at the last follow-up.
CONCLUSION: Our study expands the clinical and molecular spectrum of NUP98-r acute leukemias and recommends FISH testing for NUP98 rearrangement on those leukemia cases without recurrent gene rearrangements and/or normal karyotype followed by molecular confirmation to improve timely diagnosis and clinical management.

Keywords:   NUP98::NSD1 ; NUP98 rearrangement; acute myeloid leukemia; mixed phenotype acute leukemia

DOI:  https://doi.org/10.1111/ijlh.14422
Haematologica. 2025 Jan 23.

Sodium-glucose co-transporter-2 inhibitor treatment-associated changes in hemoglobin level in anemic patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms.

Ali Alsugair, Saubia Fathima, Fnu Aperna, Naseema Gangat, Ayalew Tefferi.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.287032
Hematol Oncol. 2025 Jan;43(1): e70040

Comprehensive Characterization of Overt Myelofibrosis in an Asian Cohort: Phenotype, Mutation Landscape and Discordance Among Scoring Systems.

Yu-Sung Chang, Yu-Hung Wang, Chao-Hung Wei, Yu-Wen Chen, Hsing-Yu Lin, Chien-Chin Lin, Xavier Cheng-Hong Tsai, Chang-Tsu Yuan, Feng-Ming Tien, Yun-Chu Lin, Sze-Hwei Lee, Yuan-Yeh Kuo, Ming-Kai Chuang, Bor-Sheng Ko, Ming Yao, Hwei-Fang Tien, Wen-Chien Chou, Hsin-An Hou.

  Various prognostic scoring systems in myelofibrosis (MF) have been developed to guide clinical decision-making in MF. However, discrepancies between different scoring systems for individual patients remain poorly understood, which can result in conflicting treatment recommendations. Moreover, data regarding there applicability in Asian populations remain scarce. We conducted a retrospective analysis of patients with overt MF at National Taiwan University Hospital from November 1, 2006, to November 30, 2023. This study evaluates the distribution, concordance, and prognostic value of various scoring systems (IPSS, DIPSS, DIPSS+, MYSEC-PM, MIPSS70, MIPSS70+v2, GIPSS), focusing on the mutational landscape, particularly TP53 mutations, and cytopenic phenotypes in an Asian MF cohort. All prognostic systems effectively stratified patients by risk (p < 0.005); however, concordance between systems was low (Cohen's κ < 0.4, except for IPSS vs. DIPSS+). GIPSS demonstrated superior performance with a comparable C-index but lower Akaike and Bayesian information criterion values. Besides high-molecular risk mutations, TP53 mutations (5.2%) were associated with worse overall survival (OS) (5-year: 30% vs. 68%, p < 0.001) and a trend toward higher leukemic transformation (5-year: 22% vs. 10%, p = 0.055). Cytopenic phenotype (59%) was associated with a higher incidence of ASXL1 mutations (44% vs. 28%, p = 0.04). In multivariable analysis, elderly patients, higher-risk GIPSS, TP53 mutation and cytopenic phenotype were associated with a poorer OS. This study validated multiple prognostic scoring systems in an Asian MF cohort, with GIPSS showing superior risk stratification. Further, cytopenic phenotype and TP53 mutations were identified as independent factors linked to poorer survival.

Keywords:  TP53; cytopenia; myelofibrosis; myeloproliferative neoplasm; prognostic scoring system

DOI:  https://doi.org/10.1002/hon.70040
Leuk Res. 2025 Jan 11. pii: S0145-2126(25)00005-0. [Epub ahead of print]149 107645

A novel KMT2A::DCP1A fusion gene in acute myeloid leukemia.

Ailing Deng, Fenghong Zhang, Man Wang, Dongyun Jiang, Jiannong Cen, Mengxing Xue, Yun Wang, Xueqing Dou, Qian Wu, Xiaofei Yang, Suning Chen.



Keywords:  Acute myeloid leukemia; DCP1A; KMT2A rearrangement; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2025.107645
J Clin Invest. 2025 Jan 21. pii: e182125. [Epub ahead of print]

Sex dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling.

Xiaojing Cui, Liming Hou, Bowen Yan, Jinpeng Liu, Cuiping Zhang, Pinpin Sui, Sheng Tong, Larry Luchsinger, Avital Mendelson, Daohong Zhou, Feng-Chun Yang, Hui Zhong, Ying Liang.

  The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared to female mice. Sex-mismatched co-culture and BM transplantation showed that the male BM niche provided superior support for in vitro colony formation and in vivo hematopoietic engraftment. The co-transplantation of male stromal cells significantly enhanced engraftment in female recipients. Single-cell RNA sequencing revealed that the lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs led to the increased expression of Cxcl12. In MSC-specific Kdm5c knockout mouse model, the reduction of KDM5C in female MSCs enhanced MSC quantity and function, ultimately improving engraftment to the male level. Kdm5c thus plays a role in driving sexual dimorphism in the BM niche and hematopoietic regeneration. Our study unveils a sex-dependent mechanism governing BM niche regulation and its impact on hematopoietic engraftment. The finding offers potential implications for enhancing BM transplantation efficacy in clinical settings by harnessing the resource of male MSCs or targeting Kdm5c.

Keywords:  Stem cell transplantation; Stem cells; Transplantation

DOI:  https://doi.org/10.1172/JCI182125
Ann Hematol. 2025 Jan 20.

Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy.

Francesca Palandri, Filippo Branzanti, Erika Morsia, Alessandra Dedola, Giulia Benevolo, Mario Tiribelli, Eloise Beggiato, Mirko Farina, Bruno Martino, Giovanni Caocci, Novella Pugliese, Alessia Tieghi, Monica Crugnola, Gianni Binotto, Francesco Cavazzini, Elisabetta Abruzzese, Alessandro Isidori, Emilia Scalzulli, Domenico D'Agostino, Santino Caserta, Antonella Nardo, Roberto Massimo Lemoli, Daniela Cilloni, Monica Bocchia, Fabrizio Pane, Florian H Heidel, Giuseppe A Palumbo, Massimo Breccia, Elena M Elli, Massimiliano Bonifacio.

  Calreticulin (CALR) mutations are detected in around 20% of patients with primary and post-essential thrombocythemia myelofibrosis (MF). Regardless of driver mutations, patients with splenomegaly and symptoms are generally treated with JAK2-inhibitors, most commonly ruxolitinib. Recently, new therapies specifically targeting the CALR mutant clone have entered clinical investigation. To collect information on efficacy and safety of ruxolitinib in CALR-mutated patients, we report a sub-analysis of the "RUX-MF" (NCT06516406) study, comprising 135 CALR-mutated and 786 JAK2-mutated ruxolitinib-treated patients. Compared to JAK2-mutated patients, CALR-mutated patients started ruxolitinib with a more severe disease (higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis) and after a longer median time from diagnosis (2.6 versus 0.7 years, p < 0.001). At 6 months, spleen responses were numerically inferior in CALR-mutated patients, who also had significantly lower rates of symptom responses (56.1% versus 66.7%, p = 0.04).

Keywords:   CALR mutation; JAK2 mutation; Myelofibrosis; Myeloproliferative neoplasms; Ruxolitinib

DOI:  https://doi.org/10.1007/s00277-025-06204-5
Leukemia. 2025 Jan 23.

Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia.

Cedric S Tremblay, Jesslyn Saw, Feng Yan, Jacqueline A Boyle, Ovini Amarasinghe, Shokoufeh Abdollahi, Anh N Q Vo, Benjamin J Shields, Chelsea Mayoh, Hannah McCalmont, Kathryn Evans, Anna Steiner, Kevin Parsons, Matthew P McCormack, David R Powell, Nicholas C Wong, Stephen M Jane, Richard B Lock, David J Curtis.

Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable "chemo-free" treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in LMO2-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.

DOI: https://doi.org/10.1038/s41375-024-02491-5
Sci Immunol. 2025 Jan 24. 10(103): eadr0782

Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.

Katie Maurer, Cameron Y Park, Shouvik Mani, Mehdi Borji, Florian Raths, Kenneth H Gouin, Livius Penter, Yinuo Jin, Jia Yi Zhang, Crystal Shin, James R Brenner, Jackson Southard, Sachi Krishna, Wesley Lu, Haoxiang Lyu, Domenic Abbondanza, Chanell Mangum, Lars Rønn Olsen, Michael J Lawson, Martin Fabani, Donna S Neuberg, Pavan Bachireddy, Eli N Glezer, Samouil L Farhi, Shuqiang Li, Kenneth J Livak, Jerome Ritz, Robert J Soiffer, Catherine J Wu, Elham Azizi.

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded ZNF683+ CD8+ cytotoxic T lymphocytes with in vitro specificity for patient-matched AML. These cells originated primarily from the DLI product and appeared to coordinate antitumor immune responses through interaction with diverse immune cell types within the marrow microenvironment. Nonresponders lacked this cross-talk and had cytotoxic T lymphocytes with elevated TIGIT expression. Our study identifies recipient bone marrow microenvironment differences as a determinant of an effective antileukemia response and opens opportunities to modulate cellular therapy.

DOI: https://doi.org/10.1126/sciimmunol.adr0782
Blood. 2025 Jan 21. pii: blood.2024025706. [Epub ahead of print]

Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.

Charlotte Rothfuß, Tobias Baumann, Sainitin Donakonda, Bettina Brauchle, Anetta Marcinek, Christian Urban, Julia Mergner, Anna-Marie Pedde, Anna Hirschberger, Christina Krupka, Anne-Sophie Neumann, Gerulf Hänel, Camilla Merten, Rupert Öllinger, Judith S Hecker, Tanja Bauer, Christian Rudolf Schmid, Katharina S Götze, Jennifer Altomonte, Veit L Bücklein, Roland Jacobs, Roland Rad, Corinna Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy Alexander Knolle, Jan P Böttcher, Bastian Höchst.

Loss of anticancer NK cell function in AML patients is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML-blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML-blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of LCK-ERK signalling that is crucial for NK cell activation, indicating a two-layered escape of AML-blasts with low expression of NK cell-activating ligands and inhibition of NK cell signalling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcg-receptor-mediated activation with the prevention of inhibitory PGE2-signalling. This rescued NK cell function and restored the killing of AML-blasts. Thus, we identify the PGE2-LCK signalling axis as the key barrier for NK cell activation in two-layered immune escape of AML-blasts that can be targeted for immune therapy to reconstitute anti-cancer NK cell immunity in AML patients.

DOI: https://doi.org/10.1182/blood.2024025706
Ann Hematol. 2025 Jan 23.

Folate metabolism in myelofibrosis: a missing key?

Giacomo Maria Cerreto, Giulia Pozzi, Samuele Cortellazzi, Livia Micaela Pasini, Orsola Di Martino, Prisco Mirandola, Cecilia Carubbi, Marco Vitale, Elena Masselli.

  Folates serve as key enzyme cofactors in several biological processes. Folic acid supplementation is a cornerstone practice but may have a "dark side". Indeed, the accumulation of circulating unmetabolized folic acid (UMFA) has been associated with various chronic inflammatory conditions, including cancer. Additionally, by engaging specific folate receptors, folates can directly stimulate cancer cells and modulate the expression of genes coding for pro-inflammatory and pro-fibrotic cytokines.This evidence could be extremely relevant for myelofibrosis (MF), a chronic myeloproliferative neoplasm typified by the unique combination of clonal proliferation, chronic inflammation, and progressive bone marrow fibrosis. Folate supplementation is frequently associated with conventional or investigational drugs in the treatment of MF-related anemia to tackle ineffective erythropoiesis. In this review, we cover the different aspects of folate metabolism entailed in the behavior and function of normal and malignant hematopoietic cells and discuss the potential implications on the biology of myelofibrosis.

Keywords:  Chronic inflammation; Folate receptor; Folic acid; Myelofibrosis; Myeloproliferative neoplasms; One-carbon metabolism

DOI:  https://doi.org/10.1007/s00277-024-06176-y
J Clin Invest. 2025 Jan 23. pii: e180981. [Epub ahead of print]

Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome.

Alexandrine Garrigue, Laëtitia Kermasson, Sandrine Susini, Ingrid Fert, Christopher B Mahony, Hanem Sadek, Sonia Luce, Myriam Chouteau, Marina Cavazzana, Emmanuelle Six, Marie-Caroline Le Bousse-Kerdilès, Adrienne Anginot, Jean-Baptiste Souraud, Valérie Cormier-Daire, Marjolaine Willems, Anne Sirvent, Jennifer Russello, Isabelle Callebaut, Isabelle André, Julien Y Bertrand, Chantal Lagresle-Peyrou, Patrick Revy.

  Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified three young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous one base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.

Keywords:  Bone marrow; Cytokines; Genetics; Hematology; Hematopoietic stem cells

DOI:  https://doi.org/10.1172/JCI180981
Bone Marrow Transplant. 2025 Jan 22.

Impact of TP53 alteration on allogeneic hematopoietic cell transplantation outcomes for myelodysplastic syndromes.

Cuiyan Zhou, Lanping Xu, Xiaohui Zhang, Yingjun Chang, Xiaodong Mo, Yuqian Sun, Xiaojun Huang, Yu Wang.

The poor outcome of TP53 alteration has been reported in myelodysplastic syndrome (MDS) patients. However, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in TP53 alteration patients remains debated. Previous studies showed that TP53 mutations had no effect on the prognosis of patients with acute leukemia after haploidentical HSCT (haplo-HSCT). The effect of haplo-HSCT on MDS patients with TP53 alterations remains to be further elucidated. We aimed to reveal the role of TP53 alterations in the prognosis of MDS patients undergoing allo-HSCT, especially haplo-HSCT. 261 MDS patients with known TP53 status were enrolled, including thirty-seven patients with TP53 mutation/deletion (TP53mut/del). TP53mut/del patients showed a worse rate of 2-year cumulative incidence of relapse (CIR) and 2-year disease-free survival (DFS) than TP53 wild type (TP53wt) patients (46.2% vs 17.0%, P < 0.001; 41.8% vs 68.9, P < 0.001) after allo-HSCT, even for those with haplo-HSCT (CIR: P < 0.001; DFS: P = 0.002). However, the prognostic effect of TP53 alteration on overall survival (OS) was not observed in patients with haplo-HSCT (66.7% vs 75.2%, P = 0.108). Positivity of post-transplantation measurable residual disease (post-MRD) and time from diagnosis to transplantation were independent risk factors for MDS patients. TP53 alterations do not affect OS in patients undergoing haplo-HSCT requires further validation.

DOI: https://doi.org/10.1038/s41409-025-02511-7
Bone Marrow Transplant. 2025 Jan 21.

Myeloablative conditioning in cord blood transplantation for acute myeloid leukemia patients is efficacious only until age 55.

Shinichiro Oshima, Yasuyuki Arai, Tadakazu Kondo, Shingo Yano, Shigeki Hirabayashi, Naoyuki Uchida, Makoto Onizuka, Shigesaburo Miyakoshi, Masatsugu Tanaka, Satoshi Takahashi, Masayuki Hayashi, Toshiro Kawakita, Yasufumi Uehara, Shuichi Ota, Toru Izumi, Masashi Sawa, Tetsuya Nishida, Yuta Katayama, Koji Nagafuji, Koji Kato, Tatsuo Ichinohe, Yoshiko Atsuta, Masamitsu Yanada.

Umbilical cord blood transplantation (CBT) is accepted as an effective treatment for acute myeloid leukemia (AML), and reduced-intensity conditioning (RIC), rather than myeloablative conditioning (MAC) regimens allowed elderly patients to be treated safely. However, appropriate intensities of conditioning regimens are still unclear, especially for middle-aged patients. To compare outcomes after RIC and MAC regimens, we analyzed AML patients aged 16 years or older in the Japanese registry database, who underwent single cord unit CBT between 2010-2019. Median ages of the RIC group (n = 1353) and the MAC group (n = 2101) were 59 and 51 years (P < 0.001), respectively. 5-year overall survival (OS) after MAC was superior to that of RIC (38.3% vs 27.7%, P < 0.001) with lower incidence of relapse (33.9% vs 37.4%, P = 0.029) and better neutrophil engraftment (84.7% vs 75.9%, P < 0.001). Detailed subgroup analysis revealed that age at transplantation is the most important factor affecting 5-year OS in RIC and MAC. This analysis identified a threshold of 55 years, beyond which the superiority of MAC disappeared, irrespective of other factors such as disease status or performance status. In conclusion, RIC may be preferable for patients aged 56 or older in CBT for AML due to higher potential toxicities.

DOI: https://doi.org/10.1038/s41409-025-02508-2
Sci Adv. 2025 Jan 24. 11(4): eads2664

Cryo-EM structure and regulation of human NAD kinase.

Prakash P Praharaj, Yang Li, Charline Mary, Mona H Soflaee, Kevin Ryu, Dohun Kim, Diem H Tran, Trishna Dey, Harrison J Tom, Halie Rion, Muriel Gelin, Andrew Lemoff, Lauren G Zacharias, João S Patricio, Thomas P Mathews, Zhe Chen, Corinne Lionne, Gerta Hoxhaj, Gilles Labesse.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial reducing cofactor for reductive biosynthesis and protection from oxidative stress. To fulfill their heightened anabolic and reductive power demands, cancer cells must boost their NADPH production. Progrowth and mitogenic protein kinases promote the activity of cytosolic NAD kinase (NADK), which produces NADP+, a limiting NADPH precursor. However, the molecular architecture and mechanistic regulation of human NADK remain undescribed. Here, we report the cryo-electron microscopy structure of human NADK, both in its apo-form and in complex with its substrate NAD+ (nicotinamide adenine dinucleotide), revealing a tetrameric organization with distinct structural features. We discover that the amino (N)- and carboxyl (C)-terminal tails of NADK have opposing effects on its enzymatic activity and cellular NADP(H) levels. Specifically, the C-terminal region is critical for NADK activity, whereas the N-terminal region exhibits an inhibitory role. This study highlights molecular insights into the regulation of a vital enzyme governing NADP(H) production.

DOI: https://doi.org/10.1126/sciadv.ads2664
Cancer Discov. 2025 Jan 24.

Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells.

Ilana Struys, Carolina Velázquez, Joske Ubels, Charlotte L LeJeune, Markus J van Roosmalen, Axel K M Rosendahl Huber, Anais J C N van Leeuwen, Wouter Bossuyt, Bernard Thienpont, Thierry Voet, Kristel Van Calsteren, Liesbeth Lenaerts, Ruben van Boxtel, Frédéric Amant.

Chemotherapy is included in the standard of care for cancer treatment during pregnancy. However, whether prenatal exposure to maternal chemotherapy treatment has a mutagenic impact on the fetal genome, remains unexplored. Therefore, we investigated mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) from neonates born to pregnant cancer patients treated with chemotherapy, as well as healthy pregnant women and untreated pregnant cancer patients. The mutational burden in HSPCs from neonates born to untreated pregnant cancer patients and to healthy controls was similar, but increased after prenatal exposure to varying types of chemotherapy regimens. Mutational signature analyses attributed the excess mutations to clock-like processes, which are active during normal cellular aging, or to direct mutagenesis by platinum-based drugs in neonates prenatally exposed to platinum-containing regimens. Our findings in the neonatal hematopoietic compartment are consistent with mutational signatures previously identified in cells of cancer survivors directly exposed to these chemotherapeutic drugs.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1368