HMGA2 is a nonhistone chr12-binding transcriptional regulator that functions as a key determinant of stem cell and progenitor cell fate across multiple tissues. In hematopoietic stem cells (HSCs), HMGA2 expression is highly enriched in the most immature populations and promotes long-term engraftment and myeloerythroid differentiation 1. Under stress conditions, HMGA2 is phosphorylated by casein kinase 2 to facilitate HSC expansion and suppress inflammatory gene transcription 2. HMGA2 is regulated developmentally through the let-7/LIN28 axis and the BRCA1/ZNF350/CtIP repressor complex 3. Beyond normal hematopoiesis, HMGA2 is aberrantly overexpressed in multiple malignancies. In colorectal cancer, HMGA2 directly activates STAT3 transcription, promoting CCL2-mediated tumor-associated macrophage recruitment and M2 polarization 4. In acute myeloid leukemia, HMGA2+ cases display an immature transcriptional signature with upregulated G2/M checkpoint genes, conferring synthetic lethality with G2/M inhibitors 5. HMGA2 fusion genes involving PLAG1 or NFIB are recurrent oncogenic drivers in pleomorphic adenomas and cutaneous mixed tumors 6 7. In lens epithelial cells, HMGA2 modulates TGFβ/Smad and Notch signaling to promote epithelial-mesenchymal transition 8. These findings establish HMGA2 as a stem cell regulator and oncogenic driver across diverse tissues.