Knockdown of SALL4 enhances all-trans retinoic acid-induced cellular differentiation in acute myeloid leukemia cells [Gene Regulation]

March 3rd, 2015 by Liu, L., , Leung, E., Cooney, A. J., Chen, C., Rosengart, T. K., Ma, Y., Yang, J.

All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia (APL). However, it has not been useful for other types of AMLs. Here, we explored the effect of SALL4, a stem cell factor, on ATRA-induced cellular differentiation in both ATRA sensitive and resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases; while in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells (HSPCs). We reason that in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal HSPCs. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, while ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with RA receptor α (RARα) and modulates ATRA target gene expression. SALL4 is shown to recruit the lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, co-inhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy.