Npm1 mutant knock-in (Npm1c/+) and HoxBlincTg HSPCs share significantly overlapping chromatin signatures and gene expression profiles in their upregulated genes as compared to WT HSPCs, including the NPM1c+ signature HoxA/B cluster genes and homeobox oncogene Meis1. Transgenic overexpression of HoxBlinc lncRNA in hematopoietic cells led to the development of an AML-like disease by triggering HSC self-renewal and expanding myelopoiesis, similar to the phenotypes displayed by Npm1c/+ mice, while inhibition of HOXBLINC in NPM1c+ AML cells mitigates leukemogenesis. Here, MEIS1 is linked to acute myeloid leukemia.