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

Tim R Randolph

doi:10.29074/ascls.18.1.38

This article has a correction. Please see:

“Advances in Understanding the Biology and Genetics of Acute Myelocytic Leukemia” and “Chronic Myelocytic Leukemia-Part I: History, Clinical Presentation, and Molecular Biology” - July 01, 2005

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Tim R Randolph, MS CLS (NCA)⇑
1. is an assistant professor in the Department of Clinical Laboratory Science, Doisy School of Allied Health Professions, Saint Louis University Health Sciences Center, St Louis MO

Address for correspondence: Tim R Randolph, 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. (314) 977-8518, (314) 977-8503 (fax). Randoltr{at}slu.edu

Following careful study of this review, the reader will be able to:

Discuss the first scientific description of CML;
Discuss the history of the Philadelphia chromosome to include the discovery of the “minute” chromosome 22 and the t(9;22) reciprocal translocation;
Describe the clinical and laboratory features of CML;
Sketch the t(9;22) translocation that produces the Philadelphia chromosome;
Describe the molecular biology of the four primary BCR/ABL fusion genes to include the four discrete breakpoints and the resulting gene arrangements;
Discuss the leukemogenic mechanisms in CML involving the BCR/ABL fusion protein; and
Compare three different versions of the fusion protein and discuss disease associations.

Abstract

DATA SOURCES: Current literature.

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 9 and the ABL protooncogene from chromosome 22. 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.

ABBREVIATIONS: ABL = Ableson oncogene found in a strain of mouse leukemia virus; ALL = acute lymphocytic leukemia; BCR = breakpoint cluster region; CML = chronic myelocytic (myelogenous) leukemia; FAB = French-American-British; FAK = focal adhesion kinase; GEF = GDP-GTP exchange factor; JAK-STAT = janus kinase-signal transducers and activators of transcription; PI-3 Kinase = phosphoinositide-3 kinase; RAC GAP = RAS-like GTPase GTP activator; WHO = World Health Organization.