Biology subjects

Milyavsky, M.

Publications and source records attributed to Milyavsky, M..

4 recordsLinked to original sources

bioRxiv2026

Sustained exposure to CAR-T cell secretome impairs human Hematopoietic Stem Cell function and is reversible by dual TNFα-IFNγ blockade

Prolonged cytopenias are a frequent complication of chimeric antigen receptor (CAR) T-cell therapies and are associated with increased infection risk and non-relapse mortality. Although inflammatory cytokines released during CAR-T cell activation have been implicated in immune effector cell-associated hematotoxicity (ICAHT), their direct effects on human hematopoietic stem and progenitor cells (HSPCs) function remains incompletely understood. Here, we established a reductionist model of CAR-T-associated hematotoxicity using conditioned media (CM) derived from activated CD19 CAR-T cells. Sustained exposure of human HSPCs to CAR-T-derived inflammatory secretome impaired HSPC expansion and reduced long-term repopulating capacity in xenotransplantation assays. In contrast, short-term exposure did not abrogate HSPC function, indicating that brief inflammatory signals can initiate durable reprogramming events, with functional consequences emerging during subsequent proliferative expansion. Mechanistically, CAR-T CM induced IFN{gamma}- and TNF-responsive transcriptional programs in HSPCs and promoted inflammatory myeloid skewing without evidence of apoptosis-dependent stem cell loss. Combined inhibition of IFN{gamma} and TNF restored HSPC expansion, normalized lineage output, reversed inflammatory transcriptional signatures, and rescued in vivo repopulating capacity without impairing CAR-T cytotoxic activity. These findings demonstrate that CAR-T-derived inflammatory signaling can directly impair human HSC function and identify dual TNF/ IFN{gamma} blockade as a potential strategy to mitigate CAR-T-associated hematotoxicity while preserving antitumor efficacy.

cell biology↗

bioRxiv2023

Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival and regeneration via cAMP/PKA pathway

Ionizing radiation (IR) and chemotherapies severely impair hematopoietic stem and progenitor cell (HSPC) function, causing bone marrow failure and secondary malignancies. Mesenchymal stromal cells (MSCs) within the hematopoietic niche support HSPC survival and regeneration, but the underlying pro-survival mechanisms remain incompletely understood. Here, we show that MSCs suppress IR-induced apoptosis in human HSPCs and preserve their regenerative capacity. Transcriptomic analyses identified a robust induction of CREB target genes in HSPCs upon MSC contact, driven by MSC-secreted prostaglandin E2 (PGE2) via cAMP signaling. While MSC-derived PGE2 predominantly protected quiescent HSPCs from IR-induced apoptosis, direct pharmacological elevation of cAMP with Forskolin/IBMX (FSKN/IBMX) effectively shielded both quiescent and cycling HSPCs, significantly enhancing their engraftment and self-renewal. Mechanistically, cAMP pathway activation reduced pro-apoptotic ASPP1 and PUMA expression, elevated p21, and stabilized anti-apoptotic MCL1 and BCL-XL proteins. Collectively, our study uncovers an MSC-driven PGE2/CREB signaling pathway critical for human HSPC regeneration, highlighting pharmacological modulation of this axis as a promising strategy to mitigate DNA damage-induced myelosuppression and improve transplantation outcomes.

cell biology↗

bioRxiv2022

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. AML exhibits epigenetic deregulation and transcriptional plasticity that contributes to pathogenesis. KDM6 proteins are histone-3 lysine-27 demethylases that play major context dependent roles in AML evolution and therapy resistance. Here, we demonstrate that KDM6 demethylase function critically regulates DNA damage repair (DDR) gene expression programs in AML. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress, with deficiency of KDM6A (UTX) and KDM6B (JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations have been implicated in chemoresistance, although a significant percentage of relapsed AML have upregulated KDM6A. Based on these mechanistic findings, olaparib treatment significantly reduced engraftment of patient-derived xenografts. Thus KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6A loss was accompanied with a downregulated BCL2A1, which is commonly associated with venetoclax resistance. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying acquired KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity, and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

cancer biology↗

bioRxiv2019

Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs)1. While substantial progress has been made to define the causal somatic mutation profile for MPNs2, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers3. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function.

genetics↗