The SH2 domain of bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype.
Bcr-Abl plays a critical role in the pathogenesis of chronic myelogenous leukemia (CML). It was previously shown that expression of Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces a myeloproliferative disorder (MPD) in mice resembling human CML. This in vivo experimental system allows the direct determination of the effect of specific domains of Bcr-Abl, or specific signaling pathways, on the complex in vivo pathogenesis of CML. In this report, the function of the SH2 domain of Bcr-Abl in the pathogenesis of CML is examined using this murine model. It was found that the Bcr-Abl SH2 mutants retain the ability to induce a fatal MPD but with an extended latency compared with wild type (wt) Bcr-Abl. Interestingly, in contrast to wt Bcr-Abl-induced disease, which is rapid and monophasic, the disease caused by the Bcr-Abl SH2 mutants is biphasic, consisting of an initial B-lymphocyte expansion followed by a fatal myeloid proliferation. The B-lymphoid expansion was diminished in mixing experiments with bcr-abl/DeltaSH2 and wt bcr-abl cells, suggesting that the Bcr-Abl-induced MPD suppresses B-lymphoid expansion.
Zhang
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X
Rosenstiel Basic Medical Sciences Research Center, Department of Biochemistry, Brandeis University, Waltham, MA, USA.
Wong
R
R
Hao
S X
SX
Pear
W S
WS
Ren
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R
D016475:3T3 Cells; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D015448:Leukemia, B-Cell / Q000139:chemically induced / Q000209:etiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009196:Myeloproliferative Disorders / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D009368:Neoplasm Transplantation / Q000379:methods; D012190:Retroviridae; D014161:Transduction, Genetic; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology*
D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016044:Fusion Proteins, bcr-abl