A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice

Acute myeloid leukemia (AML) is the commonest myeloid malignancy, yet there has been little therapeutic progress for this disease in decades, and only 25–30% of patients survive long term. 1 This reflects its pathogenetic complexity and the fact that the molecular basis of its largest cytogenetic subgroup, AML with a normal karyotype (AML-NK), was obscure until recently. Recent advances in DNA sequencing have revealed that AML-NK is molecularly heterogeneous with >30 genes recurrently targeted by somatic mutations in this disease. 2 What is also evident is that each individual case of AML-NK appears to harbor only a small number of coding driver mutations, often as few as three and usually no more than five. 2 , 3 Furthermore, it is manifest that the precise combination of driver mutations in the genome of each AML impacts on its salient features, including responsiveness to treatments and prognosis. 3