CML: mechanisms of disease initiation and progression.
Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimeric BCR-ABL gene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABL during the progression of CML. In addition, we have recently found evidence for excessive interleukin-1 beta production, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.
Wetzler
M
M
Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Talpaz
M
M
Estrov
Z
Z
Kurzrock
R
R
D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D016313:Genes, abl; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D015465:Leukemia, Myeloid, Accelerated Phase / Q000235:genetics / Q000473:pathology; D009857:Oncogenes
D016207:Cytokines; D016044:Fusion Proteins, bcr-abl