INTEGRATION OF MOLECULAR AND BIOLOGICAL ABNORMALITIES IN QUEST FOR SELECTIVE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA (CML)

CML is an excellent target for development of selective treatment beca use of its highly consistent genetic abnormality t(9;22) and unique fu sion gene product, p2l0(bcr/abl), although it is not yet clear what fo rm of specific therapy might be effective. Several components of p2l0( bcr/abl) are thought to be essential for its transforming activity: Th ese include the constitutive tyrosine kinase activity of abl and the a bility of the first exon for bcr both to specifically bind to abl's SH 2 binding domain and possibly also to function as a novel type of seri ne kinase. Relatively little is yet known about what specific abnormal ities in the regulatory pathways are caused by the altered tyrosine ki nase activity of p210(bcr/abl) and other bcr/abl oncoproteins, but wha tever its precise mode of action proves to be, p2l0(bcr/abl) presumabl y somehow changes the normal pattern of phosphorylation of key regulat ory proteins in the signaling pathways so that the genes which normall y direct the orderly sequence of proliferation and maturation of the m yeloid progenitors are not properly regulated. The end results of this 'disregulation' are that there is asynchronous br discordant maturati on; relative to comparable normal progenitors, a higher proportion of CML progenitors exhibit earlier cytoplasmic and delayed nuclear matura tion. The leukemic progenitors do not proliferate more rapidly than co mparable normal progenitors or have increased ultimate proliferative p otential, but they go through one or more additional divisions during passage through the later maturation compartments and also live longer , resulting in overexpansion of the leukemic population. It is importa nt to recognize the close linkage between maturation and proliferation in designing experiments to correlate the molecular and biological ab normalities and in seeking novel therapies to selectively affect the l eukemic progenitors.