Credit: Lara Crow/NPG

The AML1 (also known as RUNX1)–ETO (also known as RUNX1T1) fusion protein that can be present in acute myeloid leukaemia (AML) is not leukaemogenic on its own, as it suppresses proliferation and reduces cell survival. Hence, AML1–ETO requires additional cooperating mutations to induce AML. A recent paper published in Blood indicates that the interaction between AML1–ETO and the transcriptional co-repressor NCOR1 is partly responsible for limiting the leukaemogenic capacity of this fusion protein.

the W692A mutant ... effectively induced oligoclonal leukaemia

Disruption of the carboxyl terminus of AML1–ETO, by either mutation or alternative splicing, results in a more leukaemogenic protein. Two proteins that interact with the C terminus of AML1–ETO are NCOR1 and the nuclear RNA- and DNA-binding protein SON, which is required for cell cycle progression. Dong-Er Zhang and colleagues have previously shown that a C663S mutation in the C terminus of AML1–ETO results in a more leukaemogenic protein that can no longer bind SON. However, the authors were unclear whether reduced binding of NCOR1 by this mutant also contributed to its leukaemogenic nature. To answer this question, the authors identified two mutants of AML1–ETO — a W692A mutant that can interact with SON but not with NCOR1, and an AE-mutNHR3 mutant that does not bind SON but that binds NCOR1. The authors used these mutants to examine the repression of AML1–ETO target genes. As expected, wild-type AML1–ETO repressed a luciferase reporter construct containing an AML1-binding site, as did the AE-mutNHR3 protein. However, the W692A mutant showed reduced repression of the luciferase construct. In agreement with these findings, expression of either wild-type AML1–ETO or AE-mutNHR3 in mouse bone marrow cells in vitro reduced their proliferation and survival. Conversely, the W692A mutant did not have these compromising effects and effectively induced oligoclonal leukaemia when transgenically expressed in mice.

Thus, the authors conclude that one of the factors that limits the leukaemogenic capacity of AML1–ETO is the interaction of proteins with the C terminus in the region of W692, and this includes NCOR1, which mediates the repression of specific genes. Whether the binding of additional factors to the C terminus of AML1–ETO is also involved in inhibiting leukaemogenesis is not yet clear, but on the basis of these data it is unlikely that SON is involved in limiting the leukaemogenic nature of AML1–ETO.