Mechanisms Of Disease Progression

One could argue that CML would not pose a clinical problem if the disease remained in the chronic phase. Clinical observation holds that the time-to-disease progression is extremely variable from patient to patient, with some individuals progressing to blast crisis within weeks from what seemed a diagnosis of standard chronic phase disease, and others remaining stable for many years, even with conventional hydroxyurea-based therapy. The mechanisms underlying disease progression are not well understood. Studies from a number of laboratories have suggested that the expression of Bcr-Abl may adversely affect several DNA repair pathways.107-111 It is thought that over time this favors the accumulation of additional genetic abnormalities, such as the inactivation of tumor suppressor genes. Another possibility is that accelerated loss of telomere length predisposes the CML cells to the acquisition of additional chromosomal abnormalities. In fact reduced telomere length correlated with an adverse prognosis.112 However, no consistent genetic abnormalities have been associated with disease progression. Deletions of the INK4A locus, resulting in inactivation of the p16 cyclin-dependent kinase inhibitor and—presumable—p14ARF, occur in approximately 50% of patients with lymphoid blast crisis, without impacting prognosis.113114 Deletion of p53 has been observed in another subset of patients115 and deletion of the retinoblastoma susceptibility gene in isolated cases.116 All these abnormalities fail to explain the most striking feature that distinguishes blastic from chronic phase CML, namely the block of differentiation. In acute myeloid leukemia (AML), the concept that two types of mutations are required to induce the disease phenotype has recently received much attention.117 According to this model, a type I mutation, such as an activating mutation of Ras or a tyro-sine kinase, leads to increased proliferation and reduced apoptosis, while differentiation is maintained. A second, type II mutation, such as the AML1-ETO fusion, affects a transcription factor that is crucial for myeloid cell differentiation. The result is a differentiation block that leads to the full AML phenotype. Experimental evidence in support of this concept has accumulated from murine leukemia models. For example, transplantation of murine bone marrow cells expressing constitutively active Flt3 into syngeneic recipients induces a myeloproliferative syndrome, but coexpression of Aml1-Eto induces acute leukemia. Similarly, transplantation of bone marrow cells expressing both Bcr-Abl and a NUP98-HOXA9 fusion protein induces AML.118 In contrast to AML, translocations involving the core-binding factors CBFp and AML1 have only occasionally been observed in blast crisis, and there is little evidence for point mutations in these key regulators of myeloid differentiation. A more attractive candidate is EVI-1/MDS-1, a transcription factor that is affected by several chromosomal aberrations, such as t(3;21)(q26;q22), inv(3)(q21q26), or t(3;3)(q21q26), that belong to the recurrent non-random abnormalities in patients with transition to blast crisis.33 In addition, increased expression of EVI-1 mRNA has been observed in patients with blast cri-sis.119 Mice transplanted with bone marrow cells expressing both Bcr-Abl and Aml1-Evi-1 develop AML, and both components of the chimeric protein are required for induction of this phenotype.120121 Very recently, an AML1-EVI-1 fusion protein has been shown to suppress the transcription factor CEBPA in AML.122 CEBPA has also been implicated by a study that showed that CEBPA expression is inhibited in blast crisis cells as a result of posttranscriptional modification by the poly (rC) binding protein hnRNP E2.123 Another transcription factor implicated in blast crisis is Wnt, whose activation in progenitor cells may endow them with increased self-renewal capacity,124 which however does not readily explain their failure to differentiate. Lastly, it should be mentioned that increased expression of Bcr-Abl protein125 and methy-lation of the ABL promoter126 have also been linked to disease progression.

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