NAMPT-mediated LMO2 deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis

LMO2 (hematopoietic transcription factor LIM domain only 2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrated that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LDB1 and activate the TAL1 complex. NAMPT/SIRT2-mediated deacetylation of LMO2 is essential for hematopoietic differentiation of induced pluripotent stem (iPS) cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX, NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.