The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase.
The effect of mutations in the Src homology 2 (SH2) domain of the BCR/ABL oncogene on leukemogenesis was tested in a quantitative murine bone marrow transduction/transplantation assay that accurately models human Philadelphia-positive B-lymphoid leukemia and chronic myeloid leukemia (CML). The SH2 domain was not required for induction of B-lymphoid leukemia in mice by BCR/ABL. Under conditions where the p190 and p210 forms of BCR/ABL induce fatal CML-like myeloproliferative disease within 4 weeks, p210 SH2 mutants induced CML-like disease in some mice only after a significant delay, with other recipients succumbing to B-lymphoid leukemia instead. In contrast, p190 BCR/ABL SH2 point and deletion mutants rapidly induced CML-like disease. These results provide the first direct evidence of significant differences in cell signaling by the Bcr/Abl tyrosine kinase between these distinct leukemias. Contrary to previous observations, high levels of phosphatidylinositol 3-kinase (PI 3-kinase) activity in primary malignant lymphoblasts and myeloid cells from recipients of marrow transduced with the BCR/ABL SH2 mutants were found. Hence, the decreased induction of CML-like disease by the p210 BCR/ABL SH2 mutants is not due to impaired activation of PI 3-kinase.
Roumiantsev
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Center for Blood Research, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
de Aos
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IE
Varticovski
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Ilaria
R L
RL
Van Etten
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RA
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D015448:Leukemia, B-Cell / Q000209:etiology; D007942:Leukemia, Experimental / Q000201:enzymology / Q000209:etiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000209:etiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017354:Point Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology; D011485:Protein Binding; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology*
D007377:Interleukin-3; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl