MLL-AF4+ infant leukemia: a microRNA affair Comment

In this issue of Blood, Malouf et al characterize 2 microRNAs (miRNAs) that are effectors of malignant transformation by the MLL-AF4 fusion protein.(1) Mixed lineage leukemia (MLL) gene fusions are the molecular hallmark of infant acute lymphoblastic leukemia (ALL) and are present in tumor cells in up to 80% of patients.(2) Detection of the gene fusion in neonatal blood spots indicates that MLL-rearranged infant ALL originates in utero. The small number of potentially cooperating genetic lesions suggests that MLL-AF4 is suffi-cient to induce infant ALL.(3) Detection of the MLL-AF4 fusion protein in CD34(+)/CD19(-) fetal hematopoietic stem or progenitor cells or in fetal cells before hematologic specification suggests that there is a window of opportunity during development for the MLL-AF4 fusion protein to immortalize hematopoietic stem and progenitor cells (HSPCs). In an earlier study, Barrett et al used a conditional invertor mouse line for cell-specific expression of an Mll-AF4 fusion protein. Targeting of Mll-AF4 in early fetal HSPCs enhanced the lymphoid potential of primed multipotent cells but was insufficient by itself to induce leukemia.

Automated summary

The study found that the MLL-AF4 fusion protein is an effector of infant acute lymphoblastic leukemia and has the opportunity to immortalize hematopoietic stem and progenitor cells during development.