SELECTIVE THERAPY OF CHRONIC MYELOID LEUKEMIA

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The major goal of this program is to define the critical differences between normal and chronic myelogenous leukemia (CML) progenitor cells in order to develop leads for new, more selective therapy. CML is an excellent target for developing selective treatment because of its highly consistent 9;22 chromosome translocation, resulting in fusion of the bcr and abl genes and a novel fusion gene product with constitutive tyrosine kinase activity, p210bcr/abl. The fused bcr/abl gene is thought to be solely responsible for all the initial manifestations of the chronic phase of CML, and thus is an excellent model of an early form of human cancer. While it is not yet known how p210bcr/abl distorts the regulatory pathways its constitutive tyrosine kinase activity is thought to alter the normal pattern of phosphorylation of key regulatory proteins in the signal transduction pathways so that the genes that direct the orderly sequence of proliferation and maturation are not properly regulated. The end result is asynchronous development of the nucleus and cytoplasm, and the cells go through more divisions than normal during their maturation. This Research Program consists of three interrelated projects directed at understanding how the bcr/abl protein distorts the signaling pathways. Project #1 focuses on identifying differences in proteins constitutively phosphorylated on tyrosine in comparable primary highly enriched normal and CML early progenitor cells. In preliminary studies, a pp62 protein constitutively phosphorylated on tyrosine has consistently been found in purified CML blast cells that is not detectable in comparable normal blasts; this protein will be purified and characterized. Project #1 also aims to design a new mathematical model of CML, and to investigate the possibility of developing a specific immunologic (T cell mediated) therapy directed at the unique bcr/abl junction amino acid sequences. The main aim of Project #2 is to understand how the phosphorylation of p210bcr/abl relates to its functions and how these phosphorylations and functions are altered in human myeloid cells expressing p210 bcr/abl compared to those on c-abl and bcr proteins in normal myeloid cells. Project #3 also aims to study the role of tyrosine phosphorylation in CML, but will focus on the enzymes catalyzing dephosphorylation, the PTPases. In particular, the interaction between PTP1B and both c-abl and P210bcr/abl will be studied, defining interaction domains and the enzymatic and biological consequences of the association. Projects #2 and #3 will initially mainly use cell lines with and without p210 to characterize the interactions, but enriched primary normal and CML blasts will also be compared. CML has often been an exemplar of human neoplasia in the past, and new findings from this research may lead to better understanding of other types of early cancers with specific genetic defects.