New understanding of the pathogenesis of CML: A prototype of early neoplasia Journal Article
| Authors: | Clarkson, B. D.; Strife, A.; Wisniewski, D.; Lambek, C.; Carpino, N. |
| Article Title: | New understanding of the pathogenesis of CML: A prototype of early neoplasia |
| Abstract: | The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210(bcr/abl). Relative to normal c-abl, p210(bcr/abl) has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease. |
| Keywords: | signal transduction; adolescent; adult; clinical article; protein phosphorylation; human cell; cell proliferation; cell death; cell survival; cell division; stem cell factor; cell structure; apoptosis; erythropoietin; bone marrow; cell maturation; granulocyte macrophage colony stimulating factor; cell differentiation; enzyme activity; cml; protein tyrosine kinase; chronic myeloid leukemia; cell lineage; stem cell; molecular cloning; cytokine; amino acid sequence; hybrid protein; protein purification; gene fusion; phosphoproteins; chromosome translocation; cell count; hematopoiesis; hematopoietic stem cell; granulocyte colony stimulating factor; cell separation; fusion proteins, bcr-abl; thrombopoietin; phosphotyrosine; blast cell; promyelocyte; etiology; growth factor receptor; gene isolation; interleukin 3; leukemia, myeloid, philadelphia-positive; humans; human; male; female; priority journal; article; discordant maturation; chromosome translocation 9; constitutive tyrosine phosphorylation; cytokine signaling pathways; kit ligand/c-kit; p210(bcr/abl) tyrosine kinase activity |
| Journal Title: | Leukemia |
| Volume: | 11 |
| Issue: | 9 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1997-09-01 |
| Start Page: | 1404 |
| End Page: | 1428 |
| Language: | English |
| PUBMED: | 9305592 |
| PROVIDER: | scopus |
| DOI: | 10.1038/sj.leu.2400751 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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37Wisniewski -
220Clarkson -
21
Lambek -
41
Strife
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