Altered mRNA translation: possible mechanism for CML disease progression.

Chronic myelogenous leukemia (CML) is a clonal disorder arising from neoplastictransformation of the hematopoietic stem cell.1 The typical clinical course of CMLinvolves progression from a protracted chronic phase (CP) to a rapidly fatal blast crisis(BC) characterized by clonal expansion of an immature population of myeloid blast cellswhich exhibit enhanced proliferative potential, reduced susceptibility to apoptosis, anddifferentiation arrest. The latter feature is typical of CML-BC as apparently normalneutrophils and late myeloid precursors accumulate in the bone marrow and peripheralblood of CML-chronic phase patients.1,2 The introduction of the Abl kinase inhibitorGleevec (imatinib mesylate or STI571) as the drug of choice in the treatment of CML islikely to have a profound effect on the course of chronic phase CML. However, in blastcrisis CML, the therapeutic effect of Gleevec is transient and relapse of the disease is themost frequent outcome.3 Thus, it remains critically important to understand the molecularmechanisms underlying progression of CML from chronic phase to blast crisis, as thisadvanced disease stage does not respond to conventional therapy and is associated with ahigh mortality rate.While there is no doubt that expression of the BCR/ABL oncoprotein in hematopoieticstem cells is the initiating event in CML, it is somewhat controversial whether BCR/ABLplays an equally essential role during disease progression or in the blast crisis disease stage.In growth factor-dependent cell lines, ectopic expression of the BCR/ABL oncoproteinis sufficient to induce factor-independent proliferation, increased survival, and differentiationarrest, a phenotype reminiscent of that of CML blast crisis cells.4,5 However, constitutiveexpression of BCR/ABL in normal primary marrow cells leads to a myeloproliferativedisorder which is, instead, reminiscent of chronic phase CML.6 Thus, it is unclear whetherBCR/ABL oncogenic activity per se accounts for CML disease progression or if secondarygenetic alterations are required. In any case, continuous expression/activity of BCR/ABLis necessary for maintaining the leukemic phenotype in mice.7,8There is evidence that genetic inactivation of p53 occurs in blast crisis CML. Althougha p53-deficient background appears to favor blastic transformation in the appropriatemouse models,9,10 mutations in the p53 gene have been detected only in the 25% of blastcrisis.11 Another recurrent mutation in blast crisis CML is the double Philadelphiachromosome, which is detected in 20% of cases.12 In addition, expression of BCR/ABLis higher in mononuclear cells from blast crisis compared to chronic phase CMLpatients,13 and growth factor-independent and differentiation-arrested cell lines expressinghigh doses of BCR/ABL develop from growth factor-dependent cells that express low levelsof the p210 BCR/ABL oncoprotein.14 Thus, high levels of BCR/ABL in the appropriatetarget cells may have a role in blastic transformation. Consistent with this, the increasedexpression of BCR/ABL during disease progression and transformation of growth factor-dependent myeloid precursor cell lines correlates with changes in gene expression, some ofwhich involve regulators of mRNA metabolism like FUS, hnRNP A1, hnRNP E2 andLa.5,14-16In particular, the increased expression of hnRNP E2 and La, two shuttling RNA bindingproteins which function as regulators of mRNA translation,17,18 suggests that BCR/ABLand, perhaps, other oncogenic tyrosine kinases, may modulate gene expression at thetranslational level.