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Genetic abnormalities in hematologic and lymphoid malignancies

Iris Schrijver, MD
James L Zehnder, MD
Athena M Cherry, PhD
Section Editors
Richard A Larson, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Alan G Rosmarin, MD


Human malignancies can be caused by a variety of mechanisms, including the inactivation of tumor suppressor genes, activation of oncogenes, and general genomic instability. The vast majority of human hematologic neoplasms are caused by the clonal expansion of a single cell that has acquired a somatic mutation in one allele of an otherwise normal gene (proto-oncogene) governing cellular maturation and division. This mutated gene, now called an oncogene, stimulates inappropriate cellular proliferation, leading to the development of cancer.

Whereas multiple, random cytogenetic abnormalities are a characteristic finding in advanced malignancies, tumor-specific chromosomal translocations contribute directly to malignant transformation. Such translocations, and other genetic abnormalities, have been described for a large number of hematopoietic and lymphoid malignancies, including the acute and chronic lymphoid and myeloid leukemias, other myeloproliferative disorders, myelodysplastic syndromes, multiple myeloma (plasma cell myeloma), and malignant lymphomas [1,2].

A classic example is the Philadelphia chromosome (Ph), the first cytogenetic abnormality identified in a human malignancy, which is present in over 90 percent of individuals with chronic myeloid leukemia (CML). Initially described in 1960 [3], this small chromosome originates from the reciprocal translocation t(9;22)(q34;q11.2), which forms a transcriptionally active fusion gene between the BCR gene on chromosome 22 and the ABL1 locus on chromosome 9 (figure 1). The chimeric protein that is encoded by the newly created BCR-ABL1 gene on the Ph chromosome is involved in leukemogenesis through its interference with normal cell cycle events, such as signal transduction and the regulation of apoptosis and cell proliferation [4]. (See "Chromosomal translocations, deletions, and inversions" and "Cellular and molecular biology of chronic myeloid leukemia".)

The BCR-ABL1 translocation is a diagnostic hallmark of CML and the only distinct chromosome abnormality seen in the chronic phase of this disorder. In addition, its presence is an important indicator of residual disease or relapse after treatment. Sensitive molecular genetic and cytogenetic methods to detect this translocation are now available for initial diagnosis and quantitative monitoring of disease status in patients with CML. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Molecular genetics of chronic myeloid leukemia", section on 'Detecting the Philadelphia chromosome or its products'.)

Because BCR-ABL1 is the most common and best studied tumor-specific translocation in the hematopoietic malignancies, we shall use this fusion gene as a model for the ability of cytogenetic and molecular genetic diagnostic tools to help us understand the pathophysiology, diagnosis, treatment, prognosis, and monitoring of disease activity in the various hematologic malignancies. Methods for molecular and cytogenetic diagnosis are summarized separately. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

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Literature review current through: Sep 2017. | This topic last updated: Feb 08, 2016.
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