OPTIONS FOR THERAPY IN CHRONIC MYELOID LEUKAEMIA

Chronic myeloid leukaemia (CML) accounts for approximately 20% of cases in leukaemia. It is characterized by a reciprocal exchange of genetic material between the long arms of chromosome 9 and 22, t(9;22)(q34;qll). The juxtaposition of the 3' sequences of the Abelson protooncogene from chromosome 9 (abl ) with the 5' sequences of the breakpoint cluster region on chromosome 22 (bcr) results in a new chimaeric bcrlabl gene located on the Ph chromosome (22q-). This is expressed as a 210kD protein (P2 10bcr/ab') with tyrosine kinase activity greater than that of the normal abl gene derived 145 kD product (P145ab'). Models have established the causal association between the bcrlabl gene and CML (McLaughlin et al, 1987; Daly et al, 1990). Although the mechanism(s) by which this is achieved is unknown, different lines of work have suggested many possibilities. CML progenitors have been shown to have diminished adhesive properties (Gordon et al, 198 7) which results in reduced contact with stromal elements, possibly releasing them from inhibitory regulatory mechanisms. Expression of the bcrlabl gene is able to confer growth factor independence on previously factor dependent cell lines (Daley & Baltimore, 1988). Furthermore, recent work has shown that P210bcr'ab' can form a complex with GRB-2ISOS proteins (Pendergast et al, 1993), possibly resulting in up-regulation of the ras signalling pathway, a finding which has been demonstrated in some P2 10bcrlab' transformed myeloid cell lines (Mandanas et al, 1993). The clinical hallmark of CML is the hyperproliferation of the bcrlabl-containing clone resulting in expansion of the myeloid compartment and suppression of normal haemopoiesis. The signs and symptoms of chronic phase CML are directly attributable to this, and evolution to a more malignant phenotype via the acquisition of further clonal genetic abnormalities may explain the progression to the accelerated and terminal blastic phases of the disorder. The haemopoietic stem cell origin of the disorder is supported by the involvement of myeloid, erythroid, megakaryocytic, Blymphoid and possibly T-lymphoid lineages (Fialkow et al, 1977; Martinet al, 1980; Nittaet al, 1985), but a number of separate lines of evidence suggest that bcrlnbl-negative stem cells are still present in patients with CML (Dunbar & Stewart, 1992). Although the use of myeloablative chemoradiotherapy and restoration of normal haemopoiesis with allogeneic bone marrow is a curative option for eligible patients, it is the presence of bcr/abl negative stem cells in a significant proportion of CML patients which provides the