Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients

Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a m ajor substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its f irst SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to th e SH3(1) domain of CRKL. They disrupt Bcr-Abl-CRKL complexes and strongly r educe the proliferation of primary CML blast cells and cell lines establish ed from Bcr-Abl-positive patients. Activation-specific antibodies against p hosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude t hat the Bcr-Abl-CRKL complexes are largely dependent on the CRKLSH3(1) doma in, that the central mitogenic cascade is down-regulated as a consequence o f the disruption of CRKLSH3(1) interactions, and that CRKL therefore contri butes to the proliferation of CML blast cells.