Schematic representation of the mechanism by which SHP-1 and SHP-2 may regulate BCR-ABL–independent IMA resistance in CML cells. BCR-ABL plays a main role in the development and progression of CML, and the interaction between BCR-ABL and other oncogenic molecules has been extensively documented in in vitro model of IMA resistance. Nonetheless, BCR-ABL–independent signaling responsible for IMA resistance in patients with CML is not completely defined. In particular, BCR-ABL regulates SET/PP2A/SHP-1 pathway through JAK2 activation, which led to an increased level of activated Lyn.^27,40  Our data show that SHP-1 down-regulation is an important factor in causing BCR-ABL–independent IMA resistance. Indeed, we demonstrate that SHP-1 regulates proliferation and apoptosis of CML cells in which BCR-ABL is turned off by TKI treatments. Moreover, we suggest that, in the absence of ABL activities, SHP-1 phosphatase plays a key role in regulating the activation status of SHP-2, another phosphatase important in leading cellular signals related to growth factor receptors, as well as a well-known activator of the ERK1-2 pathway.