Blood, 15 February 2002, Vol. 99, No. 4, pp. 1101-1102
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?
Robert Hromas
Indiana University Cancer Center
