bims-scepro 2025-07-27 papers

Issue of 2025–07–27
five papers selected by
William Grey, University of York

Blood. 2025 Jul 23. pii: blood.2024026271. [Epub ahead of print]

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis.

Yuanyuan Ji, Yi Huang, Toby Thomas, Eda Gozel Kapti, Reiko Tachibana, Jacob Alan Lark, Iryna Berezniuk, Liang Guo, Mohamed A E Ali, Karin Mims, Benjamin Kroger, Wenhuo Hu, Christopher Y Park, Stephen S Chung.

Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their self-renewal capacity during proliferative stress and leukemogenesis remain unknown. Here we show CD99, a protein upregulated in leukemia stem cells (LSCs) in acute myeloid leukemia (AML), is required for the self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, these studies demonstrate that similar to HSCs, LSCs depend on maintenance of tightly regulated protein synthesis rates.

DOI: https://doi.org/10.1182/blood.2024026271

Cell Stem Cell. 2025 Jul 10. pii: S1934-5909(25)00256-5. [Epub ahead of print]

Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.

Infencia Xavier Raj, Won Kyun Koh, Jessica Harrison, Christine R Zhang, Barbara Soares, Roberta Amato, Aishwarya Krishnan, David R O'Leary, Hassan Bjeije, Tyler M Parsons, Wentao Han, Andrew L Young, Ting Wang, Luis F Z Batista, Grant A Challen.

DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.

Keywords: DNA methylation; DNMT3A; hematopoietic stem cell; telomerase; telomere

DOI: https://doi.org/10.1016/j.stem.2025.06.010

J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02334-8. [Epub ahead of print] 110484

The ubiquitin ligase Triad1 influences myeloid leukemogenesis by regulating the integrated stress response.

Hao Wang, Francis Suh, Mariafausta Fischietti, Brian Wray, Szymon K Filip, Peter A Faull, Liping Hu, Weiqi Huang, Bin Liu, Leonidas C Platanias, Elizabeth A Eklund.

Increased expression of a set of homeodomain transcription factors, including HoxA10, characterizes an adverse prognosis subtype of acute myeloid leukemia (AML). Examples of this subtype include AML with KMT2A or MYST3/CREBBP gene rearrangements, and an AML subset with normal cytogenetics. Previously, we identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We determined that transcriptional activation of ARIH2 by HoxA10 was necessary to terminate emergency granulopoiesis during the innate immune response, but also antagonized leukemogenesis in a murine model of KMT2A-rearranged AML. Triad1 expression progressively decreases during the latent period preceding AML in this model, and Triad1-knockdown accelerates AML development. Triad1 is an E3 ubiquitin ligase, and we found knocking down Triad1 decreased protein ubiquitination in myeloid cells. Therefore, proteins with Triad1-dependent ubiquitination might regulate leukemogenesis and/or the innate immune response. By proteomic screen, we identified Triad1-dependent ubiquitination of a set of proteins that regulate the integrated stress response (ISR), including Gcn1. The ISR prevents metabolic exhaustion during sustained inflammation by decreasing total mRNA translation and global protein synthesis, while altering the translatome to correct metabolic deficiencies and inhibit apoptosis. In cells with Triad1-knockdown, we defined a translatome consistent with ISR-activation and reversed by co-knockdown of Gcn1. Gcn1-knockdown also delayed AML development in a KMT2A-rearranged murine model, and reversed effects of Triad1-knockdown on leukemogenesis. These results suggest ISR-inhibition mediates Triad1-related leukemia suppression, and activation of the ISR enhances leukemogenesis in this adverse prognosis AML subtype.

Keywords: E3 ubiquitin ligase; gene expression; innate immunity; leukemia; ubiquitination

DOI: https://doi.org/10.1016/j.jbc.2025.110484

Leukemia. 2025 Jul 24.

Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.

Stephen J F Chong, Jolin X H Lai, Kartini Iskandar, Benedict J Leong, Chuqi Wang, Yuhan Wang, Romain Guièze, Deepika Raman, Rachel H F Lim, Catherine J Wu, Wee Joo Chng, Alice M S Cheung, Charles Chuah, Matthew S Davids, Shazib Pervaiz.

Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O2.-) levels. Validating that, augmenting intracellular O2.- in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT/PKB is implicated in O2.--induced T163pMcl-1, as reducing intracellular O2.- or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies.

DOI: https://doi.org/10.1038/s41375-025-02694-4

J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.

Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.

The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.

Keywords: IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response

DOI: https://doi.org/10.1016/j.jbc.2025.110504