Leukemogenesis csbrp
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Leukemogenesis csbrp
- 1. ETIOLOGIC AND PATHOGENETICETIOLOGIC AND PATHOGENETIC FACTORS IN WHITE CELLFACTORS IN WHITE CELL NEOPLASIANEOPLASIA Dr.CSBR.Prasad, M.D.,
- 2. Etiology 1. Heredity 2. Radiation 3. Chemical and Other Exposures 4. Drugs
- 3. Etiology 1 - Heredity – Trisomy 21 [Down syndrome] – Chromosomal breakage syndromes – Kostmann syndrome – MDS – Germ-line mutations of • CCAAT/enhancer-binding protein (C/EBP ), • runt-related transcription factor 1 (RUNX1), • p53 (TP53)
- 4. Etiology 2 - Radiation –Atomic radiation [AML after 5–7 years] –Therapeutic radiation –Alkylating agents
- 5. Etiology 3 - Chemical and Other Exposures: – Exposure to benzene – AML – Smoking – Exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides - AML
- 6. Etiology 4 – Drugs: – Anticancer drugs – AML • Alkylating agent– 4–6 years after exposure, Chr# 5 and 7 • Topoisomerase II 1–3 years after exposure, chr # 11q23 – Chloramphenicol, phenylbutazone, chloroquine and methoxypsoralen - AML
- 7. Chromosomal Translocations and Other Acquired Mutations: • Nonrandom chromosomal abnormalities, most commonly translocations • The genes that are mutated or otherwise altered often play crucial roles in the development, growth, or survival of the normal counterpart of the malignant cell – MALT1/ BCL10 – BCL-6 • Oncoproteins created by genomic aberrations often block normal maturation • Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diversification.
- 8. Molecular pathogenesis of acute leukemia
- 9. Inherited Genetic Factors • Bloom syndrome • Fanconi anemia • Ataxia telangiectasia • Down syndrome (trisomy 21) • NF type I
- 10. Viruses • HTLV-1 • EBV • KSHV/HHV-8
- 11. Chronic Immune Stimulation • H. pylori infection • H. pylori infection
- 12. Others • Iatrogenic Factors – radiation therapy and certain forms of chemotherapy used to treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms • Smoking – The incidence of acute myeloid leukemia is increased 1.3- to 2-fold in smokers
Editor's Notes
- Etiology Heredity, radiation, chemical and other occupational exposures, and drugs have been implicated in the development of AML. No direct evidence suggests a viral etiology. Heredity Certain syndromes with somatic cell chromosome aneuploidy, such as trisomy 21 noted in Down syndrome, are associated with an increased incidence of AML. Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxia telangiectasia, are also associated with AML. Congenital neutropenia (Kostmann syndrome) is a disease with mutations in the granulocyte colony-stimulating factor (G-CSF) receptor and, often, neutrophil elastase that may evolve into AML. Myeloproliferative syndromes may also evolve into AML (Chap. 103). Germ-line mutations of CCAAT/enhancer-binding protein (C/EBP ), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML in some series. Radiation Survivors of the atomic bomb explosions in Japan had an increased incidence of myeloid leukemias that peaked 5–7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents. Chemical and Other Exposures Exposure to benzene, a solvent used in the chemical, plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides, have also been associated with an increased risk of AML. Drugs Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23. Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxypsoralen can result in bone marrow failure that may evolve into AML
- Heredity Certain syndromes with somatic cell chromosome aneuploidy, such as trisomy 21 noted in Down syndrome, are associated with an increased incidence of AML. Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxia telangiectasia, are also associated with AML. Congenital neutropenia (Kostmann syndrome) is a disease with mutations in the granulocyte colony-stimulating factor (G-CSF) receptor and, often, neutrophil elastase that may evolve into AML. Myeloproliferative syndromes may also evolve into AML (Chap. 103). Germ-line mutations of CCAAT/enhancer-binding protein (C/EBP ), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML in some series.
- Radiation Survivors of the atomic bomb explosions in Japan had an increased incidence of myeloid leukemias that peaked 5–7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents.
- Chemical and Other Exposures Exposure to benzene, a solvent used in the chemical, plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides, have also been associated with an increased risk of AML.
- Drugs Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23. Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxypsoralen can result in bone marrow failure that may evolve into AML.
- FIGURE 13-4 Molecular pathogenesis of acute leukemia. Acute leukemias arise from complementary mutations that block differentiation at early stages of white cell development, enhance self-renewal, and increase growth and survival. Important examples of each type of mutation are listed. BCR-ABL, breakpoint chromosomal region–Abelson kinase fusion gene; MLL, mixed-lineage leukemia gene; PML-RARα, promyelocytic leukemia–retinoic acid receptor α fusion gene.
- Bloom syndrome, Fanconi anemia, and ataxia telangiectasia, are at increased risk of acute leukemia. In addition, both Down syndrome (trisomy 21) and type I neurofibromatosis are associated with an increased incidence of childhood leukemia.
- Viruses. Three lymphotropic viruses—human T-cell leukemia virus-1 (HTLV-1), Epstein-Barr virus (EBV), and Kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8)—have been implicated as causative agents in particular lymphomas. The possible mechanisms of transformation by viruses were discussed in Chapter 7 . HTLV-1 is associated with adult T-cell leukemia/lymphoma. EBV is found in a subset of Burkitt lymphoma, 30% to 40% of Hodgkin lymphoma (HL), many B-cell lymphomas arising in the setting of T-cell immunodeficiency, and rare NK-cell lymphomas. In addition to Kaposi sarcoma, KSHV is uniquely associated with an unusual B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity.
- Chronic Immune Stimulation. Several environmental agents that cause localized chronic immune stimulation predispose to lymphoid neoplasia, which almost always arises within the inflamed tissue. Examples include the associations between H. pylori infection and gastric B-cell lymphomas ( Chapter 17 ), and gluten-sensitive enteropathy and intestinal T-cell lymphomas. This can be contrasted with HIV infection, which is associated with an increased risk of B-cell lymphomas that may arise within virtually any organ. Early in the course, T-cell dysregulation by HIV infection causes a systemic hyperplasia of germinal center B cells that is associated with an increased incidence of germinal center B-cell lymphomas. In advanced infection (acquired immunodeficiency syndrome), severe T-cell immunodeficiency further elevates the risk for B-cell lymphomas, particularly those associated with EBV and KSHV/HHV-8.