Oncogenic signaling: new insights and controversies from chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML), which is caused by the BCR-ABL fusion tyrosine kinase, is one of the most intensively studied human cancers. ABL kinase inhibitors have been spectacularly successful in treating CML, but disease persistence and acquired drug resistance can prevent eradication and cure of the leukemia. The development of better therapies will depend on a full understanding of signaling pathways in CML, facilitated by model studies using mutant mice.

Figure 1.

Schematic representation of signaling in myeloid progenitors. (A) Interferon-α (IFN-α) induces ICSBP transcription through Stat1. Increased ICSBP mediates an antileukemic effect through an unknown mechanism. (B) The BCR–ABL kinase represses ICSBP transcription through an unknown mechanism, but also activates multiple signaling pathways, including Ras-MAPK (leading to induction of Bcl-2 gene transcription), Stat5 (leading to Bcl-X gene transcription), PI3K (through a Grb2–Gab2 interaction) leading to Akt activation, and Src family kinases (Lyn and Hck). The net effect of BCR–ABL activity is to promote Bcl-2 and Bcl-X expression and to inhibit ICSBP transcription. (C) In contrast, 12/15-LO may either activate PTEN or inhibit PDK1, both regulators of Akt, leading to increased phosphorylation and cytoplasmic localization of ICSBP, an effect mediated in part through an unknown tyrosine kinase. This may increase survival in myeloid progenitors through relief of ISCBP-mediated inhibition of Bcl-2 and Bcl-X. PIP₃, phosphatidyl inositol-3,4,5-triphosphate.