Experimental hematology最新文献

Infant B-cell acute lymphoblastic leukemia (B-ALL) harboring the KMT2A-AFF1 (MLL-AF4) fusion is associated with aggressive clinical behavior and poor outcomes, yet the molecular regulators that sustain leukemic cell survival in this high-risk subtype remain incompletely defined. In this study, we analyzed public transcriptomic data sets to identify genes selectively upregulated in MLL-AF4-positive infant B-ALL and identified gremlin-1 (GREM1) as a candidate survival-associated factor. GREM1 expression was validated in primary leukemic blasts and cell lines at both the mRNA and protein levels. Functional assays showed that recombinant GREM1 enhanced leukemic cell viability, whereas GREM1 neutralization or knockdown increased cell death, as assessed by cell viability assays and 7-AAD staining. Mechanistically, GREM1 promoted activation of the PI3K/AKT signaling pathway, and genetic inhibition of PIK3CA attenuated GREM1-mediated survival effects. In a xenograft model based on pretreated leukemia cells, GREM1 neutralization reduced leukemic fitness and was associated with a survival benefit trend. Clinically, elevated GREM1 expression was associated with inferior overall and event-free survival in independent patient cohorts. Together, these findings identify GREM1 as a leukemia cell-associated regulator of survival in infant MLL-AF4-positive B-ALL and implicate PI3K/AKT signaling as a key downstream mediator, suggesting that GREM1-associated survival pathways may represent a potential vulnerability in this aggressive leukemia subtype.

In vivo IL-1β exposure elicits enhanced hematopoietic stem cell (HSC) self-renewal and myeloid priming in Tet2^KO mice, but information on how Tet2^KO affects the early transcriptional response to IL-1β is lacking. To address this, we used an inducible, in vitro model of myeloid differentiation coupled with RNA-sequencing (RNA-seq) to study the effects of Tet2^KO on short-term IL-1β stimulation. In both Tet2^KO progenitor and differentiated states, we identified baseline increases in the expression of several cytokine signaling receptors, including Il1r1, as well as increases in inflammasome components. Interaction effect modeling revealed that loss of TET2 and IL-1β stimulation collaborate, leading to significant increases in both inflammatory cytokine expression and regulators of proliferation and differentiation in the progenitor state, and elevated cytokine production in differentiated cells. We then show that IKK-complex inhibition prevents both the IL-1β induced proliferation of Tet2^KO progenitors and TNFα production in differentiated myeloid cells, highlighting a potential therapeutic target in TET2-deficient cells..

Remarkable outcomes of chimeric antigen receptor (CAR)-T cell therapy in treating hematologic malignancies have inspired parallel efforts to harness the potential of other immune cell types for CAR-based immunotherapy. These efforts aim to overcome the existing limitations of CAR-T cell therapy. In recent years, CAR-macrophages (CAR-MACs) have shown astonishing efficacy in cancer treatment, leading to the approval of several CAR-MAC products for clinical trials. The lack of T-cell receptor (TCR) expression allows them to be used in allogeneic settings and as off-the-shelf products. Within the tumor microenvironment (TME), they can suppress tumor growth via multimodal mechanisms, including CAR-dependent and CAR-independent activities. They can also remodel the TME and prime other immune cells to enhance antitumor responses. Despite these merits, obtaining a sufficient number of MACs from traditional sources is challenging or is subject to regulatory hurdles. This review explores induced pluripotent stem cells (iPSCs) as an emerging source for generating iPSC-derived CAR-MACs (CAR-iMACs). In this regard, we began with an overview of MACs and their conventional sources and discussed the advantages of iPSCs over these traditional sources. After that, the technical procedures for generating iPSCs and differentiating them into functional CAR-iMACs were comprehensively discussed. Finally, we explored the preclinical and clinical advances in CAR-iMAC therapy.