Gremlin-1 promotes leukemic survival via PI3K/AKT signaling in infant MLL-AF4-positive B-cell acute lymphoblastic leukemia.

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.