The mixed lineage leukaemia ( MLL ) gene can be fused to one of 30 different gene partners as a result of translocations involving the long arm of chromosome 11, but it is unclear whether this mutation alone can induce acute myeloid leukaemia (AML). Ono and colleagues now suggest that the leukaemogenesis that is mediated by MLL fusion proteins is a multistep process.

MLL is a nuclear protein with domains that implicate it as a transcriptional regulator as well as being involved in chromatin-modifying supercomplexes. Although diverse, the MLL fusion proteins are all oncogenic, apparently promoting leukaemia through similar mechanisms — the aberrant activation of homeobox genes. The fusion partners of MLL are either transcriptional activators (such as ENL), making activation of MLL target genes independent of MLL homodimerization, or proteins with oligomerization domains (such as SEPT6), causing unregulated dimerization and constitutive activation of MLL. However, expression of MLL fusion proteins in animals does not induce AML with the rapidity that is seen in the human disease. So Ono and colleagues investigated the idea that secondary genetic events might be involved.

The authors focused on MLL–SEPT6. SEPT6 is one of the septins, cytoplasmic proteins that are required for cytokinesis. Expression of the retrovirally expressed MLL–SEPT6 in mouse haematopoietic progenitor cells in vitro resulted in immortalization through a block in cell differentiation and increased self-renewal. Transplantation of these cells into a mouse model induced, after a long latency, a lethal myeloproliferative disease, but not AML.

MLL–SEPT6-expressing cells isolated from these animals require interleukin-3 (IL-3) for survival. Given that IL-3 independence is associated with leukaemic progression, the authors reasoned that IL-3 independence might be a cooperating lesion. They co-infected the MLL–SEPT6-expressing cells with a retrovirus expressing the mutant form of FMS-like receptor tyrosine kinase 3 (FLT3), which has also been implicated in AML and might substitute for the tyrosine-kinase survival signal normally supplied by IL-3. Co-expression of this gene led to IL-3-independent growth in vitro and the induction of AML with short latency in vivo.

Given that mutant FLT3 also cooperated with MLL–ENL, the authors surmise that MLL fusion proteins impair differentiation and enhance the self-renewal capacity of haematopoietic progenitors, and activation of FLT3 confers a proliferative and/or survival capacity.