Chronic myelogenous leukemia chromosomal abnormality

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

The first chromosome abnormality found to be associated with a cancer was the Philadelphia chromosome, which arises as a result of a reciprocal translocation between chromosomes 9 and 22 (fig. S4.4). The tumor associated with this translocation is chronic myelogenous leukemia and results from the activation of the c-abl oncogene, which is normally located on chromosome 9. 

Chronic myelogenous leukemia (CML) arises from a chromosomally abnormal hematopoietic stem cell in which a balanced translocation between the long arms of chromosomes 9 and 22, t(9 22), is observed in 90-95% of cases. This translocation results in expression of the Bcr-Abl fusion oncoprotein with a molecular weight of 210 kDa, which is constitutively expressed. The clinical symptoms and course are related to the white blood cell count and its rate of increase. Most patients with white cell counts over 50,000/ L should be treated. The goals of treatment are to reduce the... 

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124—18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic Philadelphia chromosome translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome-positive cells. It is relatively, but not completely, selective for these cells. °°... 

FIGURE 132-1. Diagram of the chromosomal translocation that results in the Philadelphia chromosome. This abnormality is encountered in 90% to 95% of patients who have chronic myelogenous leukemia. (From Fishleder AK. Oncogenes and cancer clinical applications. Cleve Clin J Med 1990 57 721-726.)... 

B. After chronic exposure, hematologic disorders such as pancytopenia, aplastic anemia, acute myelogenous leukemia, and its variants may occur. Causality is suspected for chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin s disease, and paroxysmal nocturnal hemoglobinuria. There is unproven association between benzene exposure and acute lymphoblastic leukemia, myelofibrosis, and lymphomas. Chromosomal abnormalities have been reported, although no effects on fertility have been described in women after occupational exposure. 

---