Chronic myelocytic leukemia—Part I: History, clinical presentation, and molecular biology
Department of Clinical Laboratory Science, Doisy School of Allied Health Professions, Saint Louis University Health Sciences Center, 3437 Caroline St, St Louis, MO 63104-1111, USA.Clinical laboratory science: journal of the American Society for Medical Technology 02/2005; 18(1):38-48.
DATA SYNTHESIS: Chronic myelocytic leukemia (CML) was initially described in 1845 and is considered one of the first leukemias to be discovered. Diagnosis of CML was dramatically improved with the discovery of the Philadelphia chromosome by Nowell and Hungerford in 1960. However, the rudiments of our understanding of the molecular cause of CML began in 1973 when Janet Rowley discovered that the Philadelphia chromosome is a reciprocal translocation between chromosomes 9 and 22. The leukemogenic mechanisms of CML were hypothesized 20 years later when it was discovered that the t(9;22) translocation produced a fusion gene involving the BCR gene from chromosome 22 and the ABL protooncogene from chromosome 9 [corrected] Multiple breakpoints in BCR produce fusion genes that are translated into chimeric protein products of different lengths that are associated with different leukemic subtypes. CONCLUSION: Although CML has a rich history of interest to hematologists, it also represents a leukemogenic paradigm to the molecular biologist. Nearly all malignancies result from a series of mutagenic events, which culminate in full malignant transformation. However, it appears that CML results from a single mutagenic event involving the t(9;22) translocation leading to the development of the BCR/ABL fusion gene and the corresponding fusion protein. The successful transcription and translation of the BCR/ABL fusion protein led researchers to carefully study its involvement in leukemogenesis. The BCR/ABL fusion protein exhibits increased and constitutive tyrosine kinase activity that differs depending on which BCR breakpoint is expressed, resulting in varying clinical presentations.
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ABSTRACT: Human myeloid leukemias provide models of maturation arrest and differentiation therapy of cancer. The genetic lesions of leukemia result in a block of differentiation (maturation arrest) that allows myeloid leukemic cells to continue to proliferate and/or prevents the terminal differentiation and apoptosis seen in normal white blood cells. In chronic myeloid leukemia, the bcr-abl (t9/22) translocation produces a fusion product that is an activated tyrosine kinase resulting in constitutive activation cells at the myelocyte level. This activation may be inhibited by imatinib mesylate (Gleevec, STI-571), which blocks the binding of ATP to the activated tyrosine kinase, prevents phosphorylation, and allows the leukemic cells to differentiate and undergo apoptosis. In acute promyelocytic leukemia, fusion of the retinoic acid receptor-alpha with the gene coding for promyelocytic protein, the PML-RAR alpha (t15:17) translocation, produces a fusion product that blocks the activity of the promyelocytic protein, which is required for formation of the granules of promyelocytes and prevents further differentiation. Retinoic acids bind to the retinoic acid receptor (RAR alpha) component of the fusion product, resulting in degradation of the fusion protein by ubiquitinization. This allows normal PML to participate in granule formation and differentiation of the promyelocytes. In one common type of acute myeloid leukemia, which results in maturation arrest at the myeloid precursor level, there is a mutation of FLT3, a transmembrane tyrosine kinase, which results in constitutive activation of the IL-3 receptor. This may be blocked by agents that inhibit farnesyl transferase. In each of these examples, specific inhibition of the genetically altered activation molecules of the leukemic cells allows the leukemic cells to differentiate and die. Because acute myeloid leukemias usually have mutation of more than one gene, combinations of specific inhibitors that act on the effects of different specific genetic lesions promises to result in more effective and permanent treatment.
Article: Leukemias and plasma cell dyscrasias[Show abstract] [Hide abstract]
ABSTRACT: This review details major new observations in the diagnosis and treatment of leukemias and plasma cell dyscrasias that have been communicated since the last version of this work. This review is not exhaustive and may appear to some to be rather superficial. However, it should serve as an accurate index of current thinking and accomplishments. The review clearly demonstrates a trend away from traditional chemotherapeutic approaches to the leukemias and related diseases in favor of the more rational design of treatments for specific diseases based on laboratory observations. Some refer to the agents that have resulted from such an approach as targeted therapy and suggest that they represent a new era in cancer treatment, although one of the first targeted therapy agents to be conceived, synthesized and tested was 6-mercaptopurine decades ago. Furthermore, there is no cancer therapy more targeted than surgery, which has been practiced longer than any of us has lived. At any rate, whatever slogan may be used to describe current cancer treatment, it is clear that it is based on more preclinical science and more rational design than ever before. This chapter demonstrates that is certainly true for the leukemias and plasma cell dyscrasias. What has not been demonstrated yet is that better rationale has led to better results. That remains to be proven or disproven by continued observation of our treated patients.