Preclinical Studies of the Pathogenesis and Therapy of Ph+ Leukemia in Mice: A Critical Role for Gab2 and Development of a Novel Inhibitor of ABL T315I.
tyrosine kinases (TKs) are the hallmark of nearly all cases of myeloproliferative
neoplasms (MPNs). The most widely studied of these TKs is BCR-ABL1, a known direct
molecular cause of both CML and Ph+ B-ALL. The cardinal role of BCR-ABL1 in the
pathogenesis of CML came from the development of a bone marrow
transduction/transplantation mouse model, in which retrovirally-directed ... read moreexpression of
only BCR-ABL1 led to an MPN myeloproliferative disease that shared many of the features
of the human disease. This observation and other studies led to the development of
imatinib mesylate, a small molecule inhibitor of the ABL1 TK that has a long track
record of inducing hematologic and cytogenetic remissions in CML-CP patients in the
chronic phase of their disease. Despite the unquestioned success of imatinib and other
second generation TKIs in the treatment of CML, they present emerging clinical
challenges. One strategy to address the challenge of imatinib resistance is to seek a
better understanding of the molecular pathogenesis of CML. Previous work in our
laboratory has led to the identification of Tyr177 phosphorylation, and recruitment of
the GRBrb2 adaptor protein, as absolutely critical steps in the development of CML.
Further in vitro work has implicated the importance of a GRBrb2/GABab2 interaction in
BCR-ABL1- mediated transformation. In particular, genetic experiments in the context of
the mouse model of leukemogenesis were used to assess the importance of GABab2 in both
CML and Ph+ B-ALL. The most common mechanism for imatinib resistance involves point
mutations in the kinase domain of BCR-ABL1 that alter or disrupt inhibitor binding. The
kinase domain mutations that confer drug resistance have been previously described. The
development of second generation TKIs have focused largely on rational design of drugs
that bind within the kinase domain. As a result, these second-line therapies have had
some success in treating imatinib- resistant CML, but several mutations, in particular
the BCR-ABL1 T315I mutation, confer resistance to all approved drugs. We present current
work taking a different approach to the rational design of TKIs. In particular, we will
describe the pre-clinical development of a family of TKIs called switch pocket
inhibitors. The small molecule inhibitors are non-ATP competitive inhibitors that
function by stabilizing the inactive form of the BCR-ABL1 tyrosine
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Richard Van Etten.
Committee: Brent Cochran, Daniel Jay, and George Daley.
Keywords: Biology, and Physiology.read less