Chronic Myelocytic Leukemia - Part I: History, Clinical Presentation, and Molecular Biology

Clinical Laboratory Science, Winter 2005 by Randolph, Tim R

Progression of CML from the chronic phase to the accelerated and blast crisis phases generally involves additional genetic mutations. Cells dividing more rapidly than normal and containing genetic lesions, as do the myeloid cells in the chronic phase of CML, are more prone to additional genetic mutations as compared to normal cells. In addition, chemotherapy increases the rate of genetic mutations. Therefore, given the mutagenic predisposition of the 9;22 translocation and chemotherapeutic interventions, the additional mutations needed to progress from the chronic phase to the accelerated and blast crisis phases will usually occur. Some of the additional mutations responsible for progression to the accelerated and blast crisis phases of CML can be identified by karyotype analysis, while others require molecular techniques for identification. Monosomy of chromosomes 7, 17, or Y, trisomyS, 17, 19, and 21, an additional Philadelphia chromosome, and the 3;21 translocation that is sometimes encountered in acute leukemias, are examples of compounding chromosomal lesions. Additional genetic mutations, resolvable at the molecular level include p53, RB1, c-MYC, RAS, and AML-EVI-1.20 Mutations in these genes have produced proteins associated with malignant transformation in many other cancer systems.

PROPOSED LEUKEMOGENIC MECHANISM

The most widely accepted and significant leukemogenic mechanism attributed to the fusion protein involves the constitutive stimulation of tyrosine kinase. The tyrosine kinase activity affects a variety of signal transduction pathways. Various regions of the fusion protein bind and activate several adapter proteins, five of which are illustrated in Figure 4 as, from left to right, BAP-1, GRB2, CBL, SHC and CRKL. These adaptor proteins normally bind the same regions of the wild-type ABL and BCR proteins as occurs with the fusion protein. However, binding of the adaptor proteins to the fusion protein dramatically alters their normal activation cycle. As stated earlier, the coiled coil motif and the serine/threonine kinase domain at the amino terminus of BCR, up regulates the SH2 domain and inhibit SH3 domain of the ABL moiety, occupying the carboxy terminus of the fusion protein. This participates in constitutive stimulation of the tyrosine kinase activity of the fusion protein. The serine/threonine kinase domain of the BCR moiety may also contribute additional kinase activity to increase the overall rate of phosphorylation.

Increased phosphorylation of adaptor proteins stimulates several signal transduction pathways, maintaining them in the "on" position. The most important of these signal transduction pathways is the RAS pathway. The constitutive tyrosine kinase activity produced by the fusion protein results in an increased activation of RAS, a known oncogene, creating proliferation that is independent of cytokine control. It has been shown in vitro that leukemogenic transformation can be prevented in cells expressing BCR-ABL tyrosine kinase activity by inhibiting RAS pathways.30 This aberrant activation also appears to protect against the pathway of natural cell death called apoptosis. The result is malignant transformation of myeloid cells that are prone to accelerated division, reduction in apoptosis, and failure to fully differentiate.