Genetic abnormalities in hematologic and lymphoid malignancies
- Iris Schrijver, MD
Iris Schrijver, MD
- Adjunct Professor of Pathology
- Stanford University School of Medicine
- James L Zehnder, MD
James L Zehnder, MD
- Professor of Pathology and Medicine (Hematology)
- Stanford University School of Medicine
- Athena M Cherry, PhD
Athena M Cherry, PhD
- Professor of Pathology
- Stanford University School of Medicine
- Section Editors
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
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 , 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 . (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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- CHRONIC MYELOID LEUKEMIA AS A MODEL SYSTEM
- BCR and ABL1 genes
- - ABL1 gene
- - BCR gene
- - BCR/ABL1 fusion gene
- - ABL1/BCR fusion gene
- Infrequent breakpoints in BCR and ABL1
- - Clinical implications of various breakpoints
- Detection of Ph and BCR-ABL1
- Ph chromosome negative CML
- Monitoring of residual disease
- THE PH CHROMOSOME IN MALIGNANCIES OTHER THAN CML
- Acute lymphoblastic leukemia
- Acute myeloid leukemia
- Chronic neutrophilic leukemia
- Other hematologic malignancies
- ACUTE MYELOID LEUKEMIA
- MYELODYSPLASTIC SYNDROMES
- MULTIPLE MYELOMA AND MONOCLONAL GAMMOPATHY
- B LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
- T LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
- CHRONIC B CELL AND T CELL LEUKEMIAS
- Hodgkin lymphoma
- Burkitt lymphoma
- Follicular lymphoma
- Mantle cell lymphoma
- Anaplastic lymphoma