Inhibition of Grb2 and Crkl proteins results in growth inhibition of Philadelphia chromosome positive leukemic cells.

The Bcr-Abl oncoprotein is necessary for the growth of Philadelphia chromosome positive (Ph+) leukemic cells. The Bcr-Abl protein has been found to bind to SH2/SH3-containing adaptor proteins such as Grb2 and Crkl, and these complexes are believed to activate various signaling pathways. Grb2 and Crkl are important for the Bcr-Abl-mediated transformation of rat fibroblasts and murine hematopoietic cells. We have used liposomes to deliver nuclease-resistant antisense oligonucleotides (oligos) that are specific for the GRB2 or CRKL mRNA to leukemic cells to specifically downregulate Grb2 or Crkl protein expression. We found that by downregulating Grb2 or Crkl protein expression, Grb2 or Crkl antisense oligos could selectively inhibit the growth of Bcr-Abl positive cells, but not that of Bcr-Abl negative cells. Our data, together with other investigators' data, strongly indicate that Grb2 and Crkl are vital for the maintenance of cell growth in Ph+ leukemias.