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

Clinical Laboratory Science, Winter 2005 by Randolph, Tim R

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.

DATA SOURCES: Current literature.

DATA SYNTHESIS: Chronic myelocydc 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.

INDEX TERMS: BCR/ABL; chronic myelocytic leukemia; Philadelphia chromosome; t(9;22); tyrosine kinase inhibitor.

Clin Lab Sci 2005;18(1):38

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

1. Discuss the first scientific description of CML;

2. Discuss the history of the Philadelphia chromosome to include the discovery of the "minute" chromosome 22 and the t(9;22) reciprocal translocation;

3. Describe the clinical and laboratory features of CML;

4. Sketch the t(9;22) translocation that produces the Philadelphia chromosome;

5. Describe the molecular biology of the four primary BCR/ ABL fusion genes to include the four discrete breakpoints and the resulting gene arrangements;

6. Discuss the leukemogenic mechanisms in CML involving the BCR/ABL fusion protein; and

7. Compare three different versions of the fusion protein and discuss disease associations.

Chronic myelocytic leukemia (CML) is a myeloproliferative disorder that engenders scientific interest among groups as diverse as clinical hematologists, clinical laboratory professionals, molecular biologists, and oncologists. To the clinical hematologist, CML represents a common hematologie disorder requiring careful scrutiny of both clinical and diagnostic information to make informed therapeutic decisions to maintain quality patient care. To the laboratory professional, CML is known to be the first malignancy directly linked to a genetic mutation, creating a reliable diagnostic tool. Molecular biologists are intrigued by the effect of a single mutagenic event on signal transduction pathways leading to malignant transformation. Since leukemogenic transformation in CML is sufficiently accomplished by the t(9;22) translocation, the multistep mechanisms of carcinogenesis necessary in most other forms of cancer are not required in CML creating a carcinogenic paradigm to the oncologist.

LEUKEMOGENICAND THERAPEUTIC PARADIGM

Nearly all malignancies, regardless of type, are thought to be the result of a series of mutations in a progenitor cell that causes the cell to lose control of growth, differentiation, and apoptotic mechanisms resulting in full malignant transformation. When a cell line has received sufficient mutations to alter phenotype, but insufficient mutations to produce full malignant transformation, the cell line is said to be dysplastic or pre-malignant. The list and sequence of mutations commonly identified in a given cancer type seems to vary significantly between patients diagnosed with the same malignancy. This makes diagnosis and prognosis based on genetic abnormalities difficult for most malignancies. For a particular cancer type, patients will express different lists of mutations that appear at different stages during the progression of their disease. However, there are exceptions to this model and two such exceptions are hematopoietic malignancies, namely AML:M3 (also known as acute promyelocytic leukemia) and CML. In both cases it appears that a single mutation is sufficient to produce full leukemic transformation.