Translocations of the RARa gene in acute promyelocytic leukemia
1. Kurzrock R, and Talpaz M, Molecular Biology in Cancer Medicine, 2nd edn, ISBN
1853176761, Informa Health Care, 1999
Kurzrock and Talpaz describe acute promyelocytic leukemia as an abnormal condition genetically characterized by a gene fusion transcript that involves the RARa gene; the gene for the retinoic acid receptor alpha located on chromosome 17 and ProMyelocytic Leukemia (PML) of chromosome 151. The resultant fusion protein, as Kurzrock and Talpaz clarify, retains the ligand binding domains of retinoic acid receptor alpha in addition to blocking the transcription of the genes necessary for differentiation of the myeloid cells1. This leads to promyelocutic leukemogensis. Acute promyelocytic leukemia, as indicated by Kurzrock and Talpaz, is a bone marrow malignancy characterized by deficiency of mature blood cells and excess of immature blood cells referred to as promyelocytes.
Kurzrock and Talpaz note that there are various signs associated with acute promyelocytic leukemia1. These include: fatigue, haemorrhagic diathesis, and minor infections. Kurzrock and Talpaz bring to our attention that acute promyelocytic leukemia was recognized as a specific subset of acute myeloid leukemia in the early 1950s. Acute promyelocytic leukemia, according to Kurzrock and Talpaz, is a relatively rare condition; it comprises of 10% of all acute leukemias1.
The work of Kurzrock and Talpaz provides a critical review of the current comprehension of the molecular origin of malignancy. It also comprises of an extended discussion of apoptosis as well as heredity of cancers. Putting more emphasis on the molecular basis of a variety of human diseases as well as disease processes Kurzrock and Talpaz offer uniquely wide coverage of the molecular basis of numerous diseases affecting human beings with implications for translational molecular medicine. Kurzrock and Talpaz make it clear in their work that in both acute promyelocytic leukemia and acute lymphoblastic leukemia consistent translocations have been reported; these translocations results in rearrangement of TF genes1. Kurzrock and Talpaz point out that acute promyelocytic leukemia is almost uniformly linked to the t (15; 17), which integrates with the RARa gene located on chromosome 17 and the promyelocytic leukemia gene located on chromosome 151.
This integration as clarified by Kurzrock and Talpaz, results in two fusion RNA species: RARa- promyelocytic leukemia fusion and promyelocytic leukemia-RARa fusion. Kurzrock and Talpaz also note that several optional translations have also been described and these include: the t(11;17) and the t(5;17). These translocations involve the RARa gene located on chromosome 5 and also on distinct positions on chromosome 111.
Kurzrock and Talpaz point out that RARa are members of the nuclear hormone superfamily. They state that the RARa genes bind responsive elements of retinoic acid found in cellular gene promoters. Kurzrock and Talpaz make it clear that the involvement of the RARa gene located in the t(15;17) is most likely the main principle underlying the clinical responsiveness of acute promyelocytic leukemia to all-trans-retinoic acid. Through critical review of numerous studies concerning Translocations of the RARa gene in acute promyelocytic leukemia, Kurzrock and Talpaz came to a conclusion that all patients suffering from acute promyelocytic leukemia have complete response to all-trans-retinoic acid1.
Kurzrock and Talpaz conducted a critical analysis of previous studies on the subject and discovered that all patients presenting with promyelocytic leukemia were found with PML-RARa fusion protein. Kurzrock and Talpaz note that this fusion is disease specific and is involved in carcinogenesis1. In their work, Kurzrock and Talpaz assert that acute promyelocytic leukemia cells can mature and become neutrophils under the influence of all-trans-retinoic acid1. He also clarifies that the promyelocytic leukemia-RARa fusion protein posses altered transcavitation characteristics similar to those of normal RARa gene. These transcavitation properties help the fusion protein to function as a dominant oncogene1.