S100 proteins in AML: Differentiation and beyond

Abstract

In this issue of Blood, Laouedj and colleagues make a new and important contribution to our understanding of cell differentiation impairment in acute myeloid leukemia (AML) by illuminating the role of S100 proteins and Toll-like receptor (TLR) signaling.1 Although differentiation blockade has been recognized as a hallmark of AML for decades, direct therapeutic application of this concept has been limited to only a subtype of AML, acute promyelocytic leukemia (APL), in which the PML-RARA fusion protein is targeted by the differentiating agents retinoic acid and arsenic trioxide.2 The extraordinary clinical outcomes achieved by this strategy in APL have motivated efforts to pharmacologically release the differentiation block in other AML subtypes as well. Encouraging results were observed recently in patients with FLT3-ITD–mutated AML who were treated with tyrosine kinase inhibitors,3 and in preclinical models of NPM1- or IDH1-mutated AML treated with retinoic acid.4,5 However, mechanisms of cell differentiation impairment in AML remain largely unknown, and no therapy is yet available to induce differentiation across multiple AML subtypes.