Lineage-restricted dependency on an oncofetal SNHG29 -IGF2BP1 RNA axis in acute megakaryoblastic leukemia

Summary Acute megakaryoblastic leukemia (AMKL) is a rare, aggressive subtype of acute myeloid leukemia with developmental origins in early childhood. To uncover long noncoding RNAs (lncRNAs) sustaining this high-risk malignancy, we conducted CRISPR interference screens targeting lncRNAs overexpressed in primary AMKL samples. This analysis identified SNHG29 as a previously unrecognized lineage-specific dependency, whose silencing profoundly impaired leukemic proliferation and clonogenic growth in vitro and reduced leukemic burden in vivo. RNA pulldown coupled with proteomic analysis revealed that SNHG29 interacts with the oncofetal RNA-binding protein IGF2BP1, which is aberrantly expressed in AMKL. SNHG29 was required to maintain expression of IGF2BP1 target transcripts, including MYC- and E2F-driven proliferative programs, thereby reinforcing fetal transcriptional programs essential for leukemic maintenance. Pharmacologic inhibition of IGF2BP1-RNA interactions with the small-molecule BTYNB induced potent and selective cytotoxicity in patient-derived AMKL models. Together, these findings uncover a developmental co-dependency between SNHG29 and IGF2BP1 that defines a lineage-restricted oncogenic circuit and an actionable therapeutic vulnerability in AMKL.