Enhanced Survival Growth Advantage Self renewal I Impaired Differentiation
Increased Genomic Instability
Genetic and/or Functional inactivation of Tumor Suppressors p03 Rb p16-p14iARF OEBPa
FIGURE 3 A unifying mechanism of chronic myeloid leukemia (CML) disease progression. A model of CML disease progression resulting from the combined effects of BCR-ABL overexpression and BCR-ABL-dependent genomic instability. In this unifying model of disease progression that sees BCR-ABL as the key-player, the tumor suppressor PP2A will have the role of a "gatekeeper," as its activation controls and restrains BCR-ABL expression/activity, whereas its inhibition allows BCR-ABL expression to increase and induce a cascade of events that promote disease progression by enhancing survival, proliferation and self renewal, impairing differentiation and increasing genomic instability of a CD34+ CML cell clone. Abbreviations: CML, chronic myeloid leukemia; CML-CP, chronic myeloid leukemia-chronic phase; CML-BC, chronic myeloid leukemia-blast crisis.
tumor suppressors (i.e., p53 gene mutations) or lead to functional inactivation of tumor suppressor genes (i.e., homozygous deletion of ARF leading to p53 loss of function). In this regard, CML disease progression is similar to the transition from a premalignant to a frank neoplastic state in solid tumors. In contrast to CML and other hematological malignancies, in solid tumors the initiating event is often represented by inactivation of a tumor suppressor gene.
Genetic or functional inactivation of p53 seems the most common abnormality in CML blast crisis, as the p53 gene is mutated in 25% to 30% of myeloid CML blast crisis. Homozygous deletion of the p16INK4A/ARF locus, which indirectly affects p53 function, is detected in approximately 50% of CML lymphoid blast crisis, and expression of MDM2, the principal negative regulator of p53, is often more abundant in CML blast crisis mononuclear cells, compared to the corresponding chronic phase cells (22). Other mechanisms potentially leading to functional inactivation of p53 (i.e., cytoplasmic sequestration) have not been examined, making difficult a quantitation of the actual involvement of p53 in CML disease progression. In this regard, no studies have addressed directly the issue of functional inactivation of p53 in CML disease progression, and an assessment of the frequency of this mechanism seems necessary.
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