bims-scepro 2024-04-14 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2024–04–14
fiveteen papers selected by
William Grey, University of York

Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy.
Proteinase 3 depletion attenuates leukemia by promoting myeloid differentiation.
Single cell and bulk RNA expression analyses identify enhanced hexosamine biosynthetic pathway and O-GlcNAcylation in acute myeloid leukemia blasts and stem cells.
Lethal and sublethal effects of programmed cell death pathways on hematopoietic stem cells.
Variation in Mesenchymal KITL/SCF and IGF1 Expression at Middle Age Underlies Steady-State Hematopoietic Stem Cell Aging.
Applications of protein ubiquitylation and deubiquitylation in drug discovery.
An IL-1β-driven neutrophil-stromal cell axis fosters a BAFF-rich protumor microenvironment in individuals with multiple myeloma.
Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.
Aberrant stem cell and developmental programs in pediatric leukemia.
Ablation of Wnt signaling in bone marrow stromal cells overcomes microenvironment-mediated drug resistance in acute myeloid leukemia.
Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions.
Emerging strategies for prospective discovery of molecular glue degraders.
Normal and malignant cells are homogeneously distributed in the bone marrow of children.
ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
The DMT1 isoform lacking the iron-response element regulates normal and malignant hematopoiesis via NOTCH pathway activation.

bioRxiv. 2024 Mar 30. pii: 2024.03.28.587254. [Epub ahead of print]

Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy.

Jayna J Mistry, Kira A Young, Patricia A Colom Díaz, Inés Fernández Maestre, Ross L Levine, Jennifer J Trowbridge.

Clonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3a R878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-β-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo . This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced by Dnmt3a R878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3a R878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a ; Npm1 -mutant model. Thus, Dnmt3a -mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression.
Statement of Significance: Mesenchymal stromal cell senescence induced by Dnmt3a -mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.

DOI: https://doi.org/10.1101/2024.03.28.587254
Cell Death Differ. 2024 Apr 08.

Proteinase 3 depletion attenuates leukemia by promoting myeloid differentiation.

Huan Liu, Lu Sun, Hongfei Zhao, Zihan Zhao, Shiyue Zhang, Shan Jiang, Tianran Cheng, Xiaohan Wang, Tong Wang, Ya Shao, Haiyan Zhu, Huijuan Han, Yigeng Cao, Erlie Jiang, Yihai Cao, Yuanfu Xu.

Hematopoietic stem and progenitor cells (HSPCs) that have impaired differentiation can transform into leukemic blasts. However, the mechanism that controls differentiation remains elusive. Here, we show that the genetic elimination of Proteinase 3 (PRTN3) in mice led to spontaneous myeloid differentiation. Mechanistically, our findings indicate that PRTN3 interacts with the N-terminal of STAT3, serving as a negative regulator of STAT3-dependent myeloid differentiation. Specifically, PRTN3 promotes STAT3 ubiquitination and degradation, while simultaneously reducing STAT3 phosphorylation and nuclear translocation during G-CSF-stimulated myeloid differentiation. Strikingly, pharmacological inhibition of STAT3 (Stattic) partially counteracted the effects of PRTN3 deficiency on myeloid differentiation. Moreover, the deficiency of PRTN3 in primary AML blasts promotes the differentiation of those cells into functional neutrophils capable of chemotaxis and phagocytosis, ultimately resulting in improved overall survival rates for recipients. These findings indicate PRTN3 exerts an inhibitory effect on STAT3-dependent myeloid differentiation and could be a promising therapeutic target for the treatment of acute myeloid leukemia.

DOI: https://doi.org/10.1038/s41418-024-01288-4
Front Immunol. 2024 ;15 1327405

Single cell and bulk RNA expression analyses identify enhanced hexosamine biosynthetic pathway and O-GlcNAcylation in acute myeloid leukemia blasts and stem cells.

Robert Schauner, Jordan Cress, Changjin Hong, David Wald, Parameswaran Ramakrishnan.

   Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an overall poor prognosis and high relapse rate. Multiple factors including genetic abnormalities, differentiation defects and altered cellular metabolism contribute to AML development and progression. Though the roles of oxidative phosphorylation and glycolysis are defined in AML, the role of the hexosamine biosynthetic pathway (HBP), which regulates the O-GlcNAcylation of cytoplasmic and nuclear proteins, remains poorly defined.
Methods: We studied the expression of the key enzymes involved in the HBP in AML blasts and stem cells by RNA sequencing at the single-cell and bulk level. We performed flow cytometry to study OGT protein expression and global O-GlcNAcylation. We studied the functional effects of inhibiting O-GlcNAcylation on transcriptional activation in AML cells by Western blotting and real time PCR and on cell cycle by flow cytometry.
Results: We found higher expression levels of the key enzymes in the HBP in AML as compared to healthy donors in whole blood. We observed elevated O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) expression in AML stem and bulk cells as compared to normal hematopoietic stem and progenitor cells (HSPCs). We also found that both AML bulk cells and stem cells show significantly enhanced OGT protein expression and global O-GlcNAcylation as compared to normal HSPCs, validating our in silico findings. Gene set analysis showed substantial enrichment of the NF-κB pathway in AML cells expressing high OGT levels. Inhibition of O-GlcNAcylation decreased NF-κB nuclear translocation and the expression of selected NF-κB-dependent genes controlling cell cycle. It also blocked cell cycle progression suggesting a link between enhanced O-GlcNAcylation and NF-κB activation in AML cell survival and proliferation.
Discussion: Our study suggests the HBP may prove a potential target, alone or in combination with other therapeutic approaches, to impact both AML blasts and stem cells. Moreover, as insufficient targeting of AML stem cells by traditional chemotherapy is thought to lead to relapse, blocking HBP and O-GlcNAcylation in AML stem cells may represent a novel promising target to control relapse.

Keywords:  AML; NF-κB; O-GlcNAcylation; OGA; OGT; hexosamine biosynthetic pathway; leukemic stem cells; single cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2024.1327405
Exp Hematol. 2024 Apr 04. pii: S0301-472X(24)00073-0. [Epub ahead of print] 104214

Lethal and sublethal effects of programmed cell death pathways on hematopoietic stem cells.

Yuta Yamada, Zhiqian Zheng, Alaa K Jad, Masayuki Yamashita.

  Programmed cell death is an evolutionally conserved cellular process in multicellular organisms that eliminates unnecessary or rogue cells during development, infection, and carcinogenesis. Hematopoietic stem cells (HSCs) are a rare, self-renewing and multipotent cell population necessary for establishment and regeneration of the hematopoietic system. Counterintuitively, key components necessary for programmed cell death induction are abundantly expressed in long-lived HSCs, which often survive myeloablative stress by engaging pro-survival response that counteracts cell death-inducing stimuli. While HSCs are well-known for their apoptosis resistance, recent studies have revealed their unique vulnerability to certain types of programmed necrosis, such as necroptosis and ferroptosis. Moreover, emerging evidence has shown that programmed cell death pathways can be sublethally activated to cause non-lethal consequences such as innate immune response, organelle dysfunction, and mutagenesis. In this review, we summarize recent findings on how the divergent cell death programs are molecularly regulated in HSCs. We then discuss potential side effects caused by sublethal activation of programmed cell death pathways on functionality of surviving HSCs.

Keywords:  Hematopoietic stem cells; apoptosis; ferroptosis; immune cell-mediated killing; necroptosis; pyroptosis; sublethal cell death signaling

DOI:  https://doi.org/10.1016/j.exphem.2024.104214
Blood. 2024 Apr 10. pii: blood.2024024275. [Epub ahead of print]

Variation in Mesenchymal KITL/SCF and IGF1 Expression at Middle Age Underlies Steady-State Hematopoietic Stem Cell Aging.

Kira A Young, Maria A Telpoukhovskaia, Johanna Hofmann, Jayna J Mistry, Konstantinos Kokkaliaris, Jennifer J Trowbridge.

Intrinsic molecular programs and extrinsic factors including pro-inflammatory molecules are understood to regulate hematopoietic aging. This is based on foundational studies using genetic perturbation to evaluate causality. However, individual organisms exhibit natural variation in hematopoietic aging phenotypes and the molecular basis of this heterogeneity is poorly understood. Here, we generated individual single cell transcriptomic profiles of hematopoietic and non-hematopoietic cell types in five young adult and nine middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated which extrinsic regulatory cell types and factors would predict variance in these signatures between individual middle-aged mice. Decline in signaling mediated by ADIPOQ, KITL and IGF1 from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of Kitl and Igf1 in MSCs highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated pro-inflammatory cytokines including IL1, IL6, TNF and RANTES. In sum, we find that Kitl and Igf1 expression are co-regulated and variable between individual mice at middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.

DOI: https://doi.org/10.1182/blood.2024024275
J Biol Chem. 2024 Apr 04. pii: S0021-9258(24)01765-4. [Epub ahead of print] 107264

Applications of protein ubiquitylation and deubiquitylation in drug discovery.

Yilin Chen, Haoan Xue, Jianping Jin.

  The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS is involved in many important cellular processes. Several new UPS-based technologies, including molecular glue degraders and PROTACs (Proteolysis-targeting chimeras) to promote protein degradation, and DUBTACs (deubiquitinase-targeting chimeras) to increase protein stability, have been developed. By specifically inducing the interactions between different ubiquitin ligases and targeted proteins that are not otherwise related, molecular glue degraders and PROTACs degrade targeted proteins via the ubiquitin-proteasome system; in contrast, by inducing the proximity of targeted proteins to deubiquitinases, DUBTACs are created to clear degradable polyubiquitin chains to stabilize targeted proteins. In this review, we summarize the recent research progress in molecular glue degraders, PROTACs, and DUBTACs and their applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting molecular glue degraders, and new development of PROTACs. We also introduce the principle of DUBTAC and its applications. Finally, we propose a few future directions of these three technologies related to targeted protein homeostasis.

Keywords:  DUBTAC; Molecular glue; PROTAC; deubiquitination; ubiquitin; ubiquitylation

DOI:  https://doi.org/10.1016/j.jbc.2024.107264
Nat Immunol. 2024 Apr 10.

An IL-1β-driven neutrophil-stromal cell axis fosters a BAFF-rich protumor microenvironment in individuals with multiple myeloma.

Madelon M E de Jong, Cathelijne Fokkema, Natalie Papazian, Ágnes Czeti, Marjolein K Appelman, Michael Vermeulen, Teddie van Heusden, Remco M Hoogenboezem, Gregory van Beek, Sabrin Tahri, Mathijs A Sanders, Pieter C van de Woestijne, Francesca Gay, Philippe Moreau, Maike Büttner-Herold, Heiko Bruns, Mark van Duin, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo.

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.

DOI: https://doi.org/10.1038/s41590-024-01808-x
Cell Rep Med. 2024 Mar 23. pii: S2666-3791(24)00131-9. [Epub ahead of print] 101485

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Cameron G Hollands, Allison L Boyd, Xueli Zhao, Jennifer C Reid, Charisa Henly, Amro ElRafie, David Boylan, Emily Broder, Olivia Kalau, Paige Johnson, Alyssa Mark, Jamie McNicol, Anargyros Xenocostas, Tobias Berg, Ronan Foley, Michael Trus, Brian Leber, Alejandro Garcia-Horton, Clinton Campbell, Mickie Bhatia.

  Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Keywords:  Regen71; acute myeloid leukemia; chemotherapy; injury; leukemia stem cells; non-canonical regeneration; regeneration enriched cells; relapse

DOI:  https://doi.org/10.1016/j.xcrm.2024.101485
Front Cell Dev Biol. 2024 ;12 1372899

Aberrant stem cell and developmental programs in pediatric leukemia.

Rebecca E Ling, Joe W Cross, Anindita Roy.

  Hematopoiesis is a finely orchestrated process, whereby hematopoietic stem cells give rise to all mature blood cells. Crucially, they maintain the ability to self-renew and/or differentiate to replenish downstream progeny. This process starts at an embryonic stage and continues throughout the human lifespan. Blood cancers such as leukemia occur when normal hematopoiesis is disrupted, leading to uncontrolled proliferation and a block in differentiation of progenitors of a particular lineage (myeloid or lymphoid). Although normal stem cell programs are crucial for tissue homeostasis, these can be co-opted in many cancers, including leukemia. Myeloid or lymphoid leukemias often display stem cell-like properties that not only allow proliferation and survival of leukemic blasts but also enable them to escape treatments currently employed to treat patients. In addition, some leukemias, especially in children, have a fetal stem cell profile, which may reflect the developmental origins of the disease. Aberrant fetal stem cell programs necessary for leukemia maintenance are particularly attractive therapeutic targets. Understanding how hijacked stem cell programs lead to aberrant gene expression in place and time, and drive the biology of leukemia, will help us develop the best treatment strategies for patients.

Keywords:  development genes; fetal oncogenes; gene regulation; leukemia; stem cells

DOI:  https://doi.org/10.3389/fcell.2024.1372899
Sci Rep. 2024 04 10. 14(1): 8404

Ablation of Wnt signaling in bone marrow stromal cells overcomes microenvironment-mediated drug resistance in acute myeloid leukemia.

Hamenth Kumar Palani, Saravanan Ganesan, Nithya Balasundaram, Arvind Venkatraman, Anu Korula, Aby Abraham, Biju George, Vikram Mathews.

The survival of leukemic cells is significantly influenced by the bone marrow microenvironment, where stromal cells play a crucial role. While there has been substantial progress in understanding the mechanisms and pathways involved in this crosstalk, limited data exist regarding the impact of leukemic cells on bone marrow stromal cells and their potential role in drug resistance. In this study, we identify that leukemic cells prime bone marrow stromal cells towards osteoblast lineage and promote drug resistance. This biased differentiation of stroma is accompanied by dysregulation of the canonical Wnt signaling pathway. Inhibition of Wnt signaling in stroma reversed the drug resistance in leukemic cells, which was further validated in leukemic mice models. This study evaluates the critical role of leukemic cells in establishing a drug-resistant niche by influencing the bone marrow stromal cells. Additionally, it highlights the potential of targeting Wnt signaling in the stroma by repurposing an anthelmintic drug to overcome the microenvironment-mediated drug resistance.

DOI: https://doi.org/10.1038/s41598-024-58860-8
bioRxiv. 2024 Mar 27. pii: 2024.03.22.586349. [Epub ahead of print]

Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions.

Brandon J Czowski, Katharine A White.

Intracellular pH (pHi) dynamics are linked to cell processes including proliferation, migration, and differentiation. The adherens junction (AJ) and signaling protein β-catenin has decreased abundance at high pHi due to increased proteasomal-mediated degradation. However, the effects of low pHi on β-catenin abundance and functions have not been characterized. Here, we show that low pHi stabilizes β-catenin in epithelial cells using population-level and single-cell assays. β-catenin abundance is increased at low pHi and decreased at high pHi. We also assay single-cell protein degradation rates to show that β-catenin half-life is longer at low compared to high pHi. Importantly, we show that AJs are not disrupted by β-catenin loss at high pHi due to rescue by plakoglobin. Finally, we show that low pHi increases β-catenin transcriptional activity in single cells and is indistinguishable from a Wnt-on state. This work characterizes pHi as a rheostat regulating β-catenin abundance, stability, and funcion and implicates β-catenin as a molecular mediator of pHi-dependent cell processes.
Summary: Intracellular pH (pHi) regulates the degradation rate of the pH sensor β-catenin, altering protein abundance, localization, and function in epithelial cells. This work shows pHi acts as a rheostat to alter both adhesion and signaling functions of β-catenin.

DOI: https://doi.org/10.1101/2024.03.22.586349
Curr Opin Struct Biol. 2024 Apr 09. pii: S0959-440X(24)00038-1. [Epub ahead of print]86 102811

Emerging strategies for prospective discovery of molecular glue degraders.

Baiyun Wang, Shiyun Cao, Ning Zheng.

Molecular glue (MG) degraders are monovalent small molecule compounds that co-opt E3 ubiquitin ligases to target neo-substrates for proteasomal degradation. Here, we provide a concise review of recent advances in rational MG discovery, which are categorized into two major strategies, ligand modification and de novo discovery. We also highlight the structural mechanisms underlying the formation of MG-enabled ternary complexes and their thermodynamic properties. Finally, we summarize the broader category of proximity inducers including MGs, proteolysis-targeting chimeras (PROTACs), peptides, and viral proteins. MGs are specified as a unique class of proximity inducers with chemical simplicity and a requirement of pre-existing weak protein-protein interactions. We propose that leveraging the weak basal interaction provides a starting point to prospectively develop MGs to degrade high-value therapeutic targets.

DOI: https://doi.org/10.1016/j.sbi.2024.102811
Leuk Lymphoma. 2024 Apr 08. 1-4

Normal and malignant cells are homogeneously distributed in the bone marrow of children.

Sharon Veenbergen, Romana Jugooa, Jeroen Te Marvelde, Andrica C H de Vries, Vincent H J van der Velden.

DOI: https://doi.org/10.1080/10428194.2024.2337782
Nature. 2024 Apr 10.

ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.

Gang Du, Liam B Healy, Liron David, Caitlin Walker, Tarick J El-Baba, Corinne A Lutomski, Byoungsook Goh, Bowen Gu, Xiong Pi, Pascal Devant, Pietro Fontana, Ying Dong, Xiyu Ma, Rui Miao, Arumugam Balasubramanian, Robbins Puthenveetil, Anirban Banerjee, Hongbo R Luo, Jonathan C Kagan, Sungwhan F Oh, Carol V Robinson, Judy Lieberman, Hao Wu.

Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD is also palmitoylated after inflammasome stimulation or treatment with ROS activators, and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated in their N-termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family.

DOI: https://doi.org/10.1038/s41586-024-07373-5
FEBS Lett. 2024 Apr 09.

The DMT1 isoform lacking the iron-response element regulates normal and malignant hematopoiesis via NOTCH pathway activation.

Judith Hounjet, Linde Van Aerschot, Kim De Keersmaecker, Marc Vooijs, Kim R Kampen.

  Natural resistance-associated macrophage protein 2 (NRAMP 2; also known as DMT1 and encoded by SLC11A2) is mainly known for its iron transport activity. Recently, the DMT1 isoform lacking the iron-response element (nonIRE) was associated with aberrant NOTCH pathway activity. In this report, we investigated the function of DMT1 nonIRE in normal and malignant hematopoiesis. Knockdown of Dmt1 nonIRE in mice showed that it has non-canonical functions in hematopoietic stem cell differentiation: its knockdown suppressed development along the myeloid and lymphoid lineages, while promoting the production of platelets. These phenotypic effects on the hematopoietic system induced by Dmt1 nonIRE knockdown were linked to suppression of Notch/Myc pathway activity. Conversely, our data indicate a non-canonical function for DMT1 nonIRE overexpression in boosting NOTCH pathway activity in T-cell leukemia homeobox protein 1 (TLX1)-defective leukemia. This work sets the stage for future investigation using a multiple-hit T-cell acute lymphoblastic leukemia (T-ALL) model to further investigate the function of DMT1 nonIRE in T-ALL disease development and progression.

Keywords:  DMT1; NOTCH; T‐ALL; T‐cell leukemia; differentiation; hemtapoiesis

DOI:  https://doi.org/10.1002/1873-3468.14870