Gabbing about blast crisis

BCR-ABL, the protein product of the t(9;22) translocation in chronic myelogenous leukemia (CML), is a deregulated tyrosine kinase. Tyrosine kinases connect with docking proteins to transfer growth signals to downstream effectors and, eventually, to transcription factors that then modify gene expression patterns and change a cell's behavior. BCR-ABL signals through PI3kinase, STAT5, and Ras to stimulate myeloid stem and progenitor cells to proliferate abnormally. But these excess myeloid progenitors continue to differentiate to mature blood cells during the chronic phase of CML.

Unfortunately, CML terminates in a blast crisis in which the myeloid progenitors no longer differentiate but rapidly proliferate as a refractory acute leukemia. The additional molecular lesions besides the t(9;22) that lead to blast crisis are not well defined. Dorsey and colleagues (page 1388) provide evidence that Gab2 may be one such molecular lesion in blast crisis. Gab2 is a docking protein that transfers the BCR-ABL signal to the Erk MAP kinase downstream effectors. Erk MAP kinase is known to mediate terminal myeloid differentiation, yet its activity is conspicuously absent in CML blast crisis cells. Inducible overexpression of Gab2 in blast crisis cell lines stimulates their growth arrest and terminal differentiation. This overexpression can activate promoters that are known end results of the Erk MAP kinase pathway, further implicating Gab2 in mediating gene expression changes in myeloid differentiation in BCR-ABL–positive cells.

Several intriguing questions are raised by this study. Is Gab2 activity consistently missing in primary CML blast crisis leukemia cells? If so, what are the mutations that lead to its decreased activity? Gab2 may be involved in cryptic translocations, or there may be inactivating point mutations acquired in Gab2 during transformation to blast crisis. Finally, would blast crisis acute leukemias, notoriously difficult to treat, respond to a therapy that restores Gab2 activity?