Up a lymphoid blind alley: Does CALM/AF10 disturb Ikaros during leukemogenesis?

The Ikaros gene is required for normal development of lymphocytes and frequent intragenic deletions of Ikaros have been identified in acute lymphoblastic leukemia. However, little is known about the role of Ikaros in myeloid malignancies. Here we discuss the role of Ikaros as a lineage master regulator during the onset and progression of myeloid leukemias, namely CALM-AF10 positive acute myeloid leukemia and chronic myeloid leukemia. Alterations of Ikaros at the gene or protein level may act as a bi-directional lineage switch subverting developmental plasticity for malignant transformation. Finally, we propose that promiscuous signaling involving Ikaros and FOXO transcription factors might be a critical link between early lineage fate and uncontrolled proliferation.