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Chronic myelogenous leukemia: molecular and cellular aspects.
J Cancer Res Clin Oncol 1998; 124(12):643-60JC

Abstract

Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoietic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoietic cell lineages are involved in the process of clonal proliferation and differentiation. After a period of 4-6 years the disease progresses to acute-stage leukemia. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. Most of ABL is linked with a truncated BCR. The BCR/ABL fusion gene codes for an 8-kb mRNA and a novel 210-kDa protein which has higher and aberrant tyrosine kinase activity than the normal c-ABL-coded counterpart. Phosphorylation of a number of substrates such as GAP, GRB-2, SHC, FES, CRKL, and paxillin is considered a decisive step in transformation. An etiological connection between BCR/ABL and leukemia is indicated by the observation that transgenic mice bearing a BCR/ABL DNA construct develop leukemia of B, T, and myeloid cell origin. CML cells proliferate and expand in an almost unlimited manner. Adhesion defects in bone marrow stromal cells have been proposed to explain the increased number of leukemic cells in the peripheral blood. However, findings of our laboratory have shown that the BCR/ABL chimeric protein that is expressed in transfected cells may, under certain conditions, also increase the adhesion to fibronectin via enhanced expression of integrin. Our previous immunocytological studies on the expression of beta1 and beta2 integrins have found no qualitative differences between normal and CML hematopoietic cells in vitro. Even long-term-cultured CML bone marrow or blood cells continuously express those adhesion molecules that are characteristic of the cytological type. Recent experiments indicate that certain early CML progenitors may adhere to the stromal layer in vitro similarly to their normal counterparts. They cannot be completely removed by long-term culture on allogeneic stromal cells. At present, the only curative therapy is transplantation of allogeneic hematopoietic stem cells. Based on the molecular and cellular state of knowledge of CML, new therapies are being developed. BCR/ABL antisense oligonucleotides, inhibitors of tyrosine kinase, peptide-specific adoptive immunotherapy or peptide vaccination, and restoration of hematopoiesis by autologous stem cell transplantation following CML cell purging are examples of important approaches to improving CML treatment.

Authors+Show Affiliations

III. Medizinische Klinik, Klinikum Mannheim der Universität Heidelberg, Mannheim, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

9879825

Citation

Pasternak, G, et al. "Chronic Myelogenous Leukemia: Molecular and Cellular Aspects." Journal of Cancer Research and Clinical Oncology, vol. 124, no. 12, 1998, pp. 643-60.
Pasternak G, Hochhaus A, Schultheis B, et al. Chronic myelogenous leukemia: molecular and cellular aspects. J Cancer Res Clin Oncol. 1998;124(12):643-60.
Pasternak, G., Hochhaus, A., Schultheis, B., & Hehlmann, R. (1998). Chronic myelogenous leukemia: molecular and cellular aspects. Journal of Cancer Research and Clinical Oncology, 124(12), pp. 643-60.
Pasternak G, et al. Chronic Myelogenous Leukemia: Molecular and Cellular Aspects. J Cancer Res Clin Oncol. 1998;124(12):643-60. PubMed PMID: 9879825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic myelogenous leukemia: molecular and cellular aspects. AU - Pasternak,G, AU - Hochhaus,A, AU - Schultheis,B, AU - Hehlmann,R, PY - 1999/1/8/pubmed PY - 1999/1/8/medline PY - 1999/1/8/entrez SP - 643 EP - 60 JF - Journal of cancer research and clinical oncology JO - J. Cancer Res. Clin. Oncol. VL - 124 IS - 12 N2 - Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoietic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoietic cell lineages are involved in the process of clonal proliferation and differentiation. After a period of 4-6 years the disease progresses to acute-stage leukemia. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. Most of ABL is linked with a truncated BCR. The BCR/ABL fusion gene codes for an 8-kb mRNA and a novel 210-kDa protein which has higher and aberrant tyrosine kinase activity than the normal c-ABL-coded counterpart. Phosphorylation of a number of substrates such as GAP, GRB-2, SHC, FES, CRKL, and paxillin is considered a decisive step in transformation. An etiological connection between BCR/ABL and leukemia is indicated by the observation that transgenic mice bearing a BCR/ABL DNA construct develop leukemia of B, T, and myeloid cell origin. CML cells proliferate and expand in an almost unlimited manner. Adhesion defects in bone marrow stromal cells have been proposed to explain the increased number of leukemic cells in the peripheral blood. However, findings of our laboratory have shown that the BCR/ABL chimeric protein that is expressed in transfected cells may, under certain conditions, also increase the adhesion to fibronectin via enhanced expression of integrin. Our previous immunocytological studies on the expression of beta1 and beta2 integrins have found no qualitative differences between normal and CML hematopoietic cells in vitro. Even long-term-cultured CML bone marrow or blood cells continuously express those adhesion molecules that are characteristic of the cytological type. Recent experiments indicate that certain early CML progenitors may adhere to the stromal layer in vitro similarly to their normal counterparts. They cannot be completely removed by long-term culture on allogeneic stromal cells. At present, the only curative therapy is transplantation of allogeneic hematopoietic stem cells. Based on the molecular and cellular state of knowledge of CML, new therapies are being developed. BCR/ABL antisense oligonucleotides, inhibitors of tyrosine kinase, peptide-specific adoptive immunotherapy or peptide vaccination, and restoration of hematopoiesis by autologous stem cell transplantation following CML cell purging are examples of important approaches to improving CML treatment. SN - 0171-5216 UR - https://www.unboundmedicine.com/medline/citation/9879825/Chronic_myelogenous_leukemia:_molecular_and_cellular_aspects_ L2 - https://dx.doi.org/10.1007/s004320050228 DB - PRIME DP - Unbound Medicine ER -