NEW UNDERSTANDING OF THE PATHOGENESIS OF CML - A PROTOTYPE OF EARLY NEOPLASIA

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210(bcr/abl). Rela tive to normal c-abl, p210(bcr/abl) has elevated tyrosine kinase activ ity that is essential for its transforming activity. We recently repor ted a prominent 62 kDa GAP-associated P-tyr protein and five additiona l consistent but loss prominent P-tyr proteins as well as five more mi nor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin-normal blasts. The GAP-associated p62 p rotein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being charact erized. In analyzing P-tyr proteins in primary lire-normal blasts in r esponse to various hematopoietic cytokines, we found a striking simila rity in the tyrosine phosphorylation of four major and three minor pro teins after stimulation with c-hit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin-chroni c phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FL T3 ligand, TPO, EPO) were much less active or stimulated phosphorylati on of other proteins, KL/c-kit and bcr/abl have some similar activitie s including enhancing survival and expansion of hematopoietic progenit or cells, probably acting primarily on early progenitors at the time o f lineage commitment rather than on self-renewing stem cells. activati on of growth factor receptors promote a cascade of protein phosphoryla tions that can ultimately result in a wide range of cellular responses . Sustained activation oi discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instea d causes a proliferative response; in other cell types, the converse i s true. It may he postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders t hem especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical reg ulatory pathways, including c-kit. The affected pathways central and c oordinate multiple diverse cell processes including proliferation, dif ferentiation, maturation and apoptosis, processes that are normally ti ghtly regulated and integrated. Perturbation oi these key pathways in primitive progenitors would be expected to seriously disrupt orderly h ematopoiesis and could also explain the multiple subtle pleiotropic bi ological abnormalities characteristically observed in later maturing C ML compartments that we have collectively designated 'discordant matur ation'. The true situation is undoubtedly very complex and involves in teraction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical path ways in susceptible early progenitors that normally require KL or othe r factors for activation could explain most if not all features of the disease.