P210 BCR-ABL EXPRESSION IN A PRIMITIVE MULTIPOTENT HEMATOPOIETIC-CELLLINE MODELS THE DEVELOPMENT OF CHRONIC MYELOID-LEUKEMIA

Chronic myeloid leukaemia (CML) is a clonal disorder of the pluripoten t haemopoietic stem cell, the hallmark of which is the constitutively activated Bcr-Abl protein tyrosine kinase. During the initial chronic phase of CML the primitive multipotent leukaemic progenitor cells rema in growth factor dependant and are capable of producing terminally dif ferentiated cells. Although the available evidence suggests that Bcr-A bl directly affects signalling pathways involved in controlling the de velopment of primitive haemopoietic progenitors the identification of the specific biological consequences of Bcr - Abl activity in these pr ogenitors has been hampered by the lack of suitable systems modelling CML, By transfecting the multipotent haemopoietic cell line FDCP-Mix w ith a temperature sensitive mutant of Bcr-Abl we have developed the fi rst working model that mirrors the chronic phase of CML, FDCP-Mix cell s expressing Bcr-Abl tyrosine kinase activity remain growth factor dep endent and retain their ability to differentiate. Normal neutrophilic cells are formed in response to CSF and GM-CSF, In addition, the trans fected FDCP-Mix cells grown at the permissive temperature for Bcr-Abl tyrosine kinase activity display enhanced survival and proliferation i n low concentrations of growth factor, These findings are consistent w ith the initial subtle changes seen in CML progenitor cells during the chronic phase and confirm that Bcr-Abl effects are context specific, i.e, they depend on the origin and developmental potential of the tran sfected cells, This questions the significance of studies in non-haemo poietic and differentiation blocked haemopoietic cells.