Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

ABSTRACT: The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis.

OTHER RELATED OMICS DATASETS IN: GSE128529 GSE128528 GSE128530

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Enrico Massignani  

LAB HEAD: Tiziana Bonaldi

PROVIDER: PXD012954 | Pride | 2020-05-26

REPOSITORIES: Pride