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

Figure 1 Model of the CALM/AF10 Ikaros interaction during leukemogenesis (adapted from Greif et al[5], 2008). Hematopoietic stem cells (HSC) give rise to multipotent progenitors (MPP) that divide into common lymphoid (CLP) and myeloid progenitors (CMP). Ikaros is required for the maturation of lymphoid progenitors. We propose that CALM/AF10 alters its subcellular localization[5] and thereby disturbs Ikaros function at this stage leading to impaired thymocyte differentiation[15] and phenotypically acute myeloid leukemia (AML) with lymphoid characteristics[8]

Figure 2 Pre-B-cell-receptor signaling is regulated by a feed-back loop via Ikaros and Aiolos. The pre-B-cell-receptor (pre-BCR)-signaling cascade also involves FOXO transcription factors which may act as an interface between early B-cell development and FLT3-signaling that is frequently altered in acute myeloid leukemia (AML)[25]. FOXO-proteins are also regulated by downstream signaling of BCR-ABL1[27]. Disruption of Ikaros function by either deletions or protein interactions may interrupt the inhibitory feed-back loop to the pre-BCR pathway and thereby enhance pre-BCR-signaling.