The Cytogeneticmolecular Events Of Transformation

Almost invariably the indolent chronic phase of CML transforms into the blast phase. This transformation is often heralded by refractoriness to treatment, leukocytosis with increases in peripheral blood and bone marrow blasts, basophilia, increases or decreases of platelet counts unrelated to therapy, or clinical signs and symptoms such as unexplained fevers, splenomegaly, extramedullary disease, weight loss, and bone and joint pains. The cytogenetic-molecular events that underlie these changes are being unraveled at an astounding pace and will provide us with more effective therapeutic means to treat these conditions that still bear a dismal prognosis.

The Ph translocation is the predominant cytogenetic abnormality during chronic phase. Other cytogenetic abnormalities are present in less than 10 to 20 percent ofpatients.11,132 Clonal evolution, that is, the acquisition of additional karyotype changes, occurs in 50 to 80 percent of patients who progress to the transformed stages. These abnormalities frequently precede the hematological and clinical manifestations of transformed CML. Only about 20 percent of patients progress to blast phase without signs of clonal evolution. Clonal evolution and its accompanying molecular events are probably facilitated by increasing genetic instability in a largely expanded mass of myeloid progenitor cells and is eventually responsible for uncoupling maturation from proliferation in the CML cells.133 Several cytogenetic abnormalities predominate in CML evo-lution.134 Some include monosomies of chromosomes 7, 17, and Y, trisomy 17 and 21, and translocation t(3;21)(q26;q22). More frequently observed are trisomy 8, isochromosome i(17q), trisomy 19, and an additional Ph chromosome (double Ph). Trisomy 8 is the most common cytogenetic abnormality of transformed CML and predominates in myeloid blast phase. It sometimes occurs in combination with isochromosome i(17q), trisomy 19, and the double Ph. Like trisomy 8, i(17q) occurs almost exclusively in myeloid-type blast phase. It is associated with trisomy 8 and trisomy 19, but not the double Ph.5,11,34,132 Multiple molecular abnormalities occur during progression of CML. These involve p53 (chromosome 17p13), RB1 (13q14), MYC (8q24), p16INK4a/p14ARF (9p21), RAS, and the AML-EVI1 fusion protein resulting from translocation t(3;21)(q26;q22).135-139 Deregulations of molecular pathways of apoptosis and the significance of telomere length and telom-erase activity are being recognized as important components of transformation. Loss of function of p53 has been associated with suppression of apoptosis and progression into blastic phase. Skorski and colleagues140 injected immunodeficient mice with p210BCR-ABL-positive, p53-negative cells and produced the phenotype of a highly aggressive, poorly differentiated acute leukemia. In contrast, injection of p210BCR-ABL-positive, p53-positive bone marrow cells caused tissue infiltrates with a more differentiated phenotype and clinically less aggressive dis-ease.140 Honda and colleagues,141 by cross-mating p210BCR-ABL transgenic mice with p53-heterozygous mice, demonstrated that mice that expressed BCR-ABL and lacked one allele for p53 had rapid proliferation of blast cells and died in a short period of time. Interestingly, they also found that the residual normal p53 allele was frequently and preferentially lost in the leukemic cells, suggesting that certain mechanisms in BCR-ABL expressing cells facilitate the loss of the normal p53 allele. Whereas abnormalities of p53 appear to occur predominantly during myeloid transformation, abnormalities of RB1 are more frequently associated with the development of a lymphoid blast phase. Although this association is weaker than it is between p53 and myeloid transformation, distinct molecular pathways may exist that selectively involve lymphoid or myeloid transformation.

Telomere shortening has been associated with disease evolution in CML. Telomeres constitute the terminal chromosome sequences whose progressive shortening is thought to be important in the regulation of cellular senescence. Through inherent inadequacies of the cellular replicative apparatus, telomeres continuously shorten during a cell's life span. In contrast, upregulation of telomerase activity in neoplastic cells may maintain an inappropriate telomere length and endow cancer cells with a prolonged life span and the possibility of repeated cell divisions.142 Normal telomere length at the time of diagnosis of patients with chronic phase CML was associated with lower frequency of transformation and a significantly higher incidence of cytogenetic responses and a favorable prognosis to interferon-alpha therapy.143 Furthermore, CML patients in blast phase were found to have a significant increase of telom-erase activity compared to patients in chronic phase CML.144 Boultwood and colleagues145 showed that age-adjusted telomere repeat array (TRA) reduction correlated significantly with time from diagnosis to acceleration. Patients with shortened telomeres entered the accelerated phase more rapidly thus providing a means to select patients with high risk of disease transformation in CML. The fact that cells from patients in transformed phases of CML have significantly shorter telomere lengths than patients in chronic phase or cytogenetic remission, also suggests that Ph-positive stem cells cycle more actively than their counterparts in normal individuals.146

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