RGD Reference Report - BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model. - Rat Genome Database

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BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model.

Authors: Lin, F  Monaco, G  Sun, T  Liu, J  Lin, H  Stephens, C  Belmont, J  Arlinghaus, RB 
Citation: Lin F, etal., Oncogene. 2001 Apr 5;20(15):1873-81.
RGD ID: 11038780
Pubmed: PMID:11313935   (View Abstract at PubMed)
DOI: DOI:10.1038/sj.onc.1204409   (Journal Full-text)

It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML). We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl. To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity. Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P<0.0001. Of interest, mice that were fed Tet for 19 days to initiate the disease syndrome and then released from the BCR transcriptional block had a significantly better survival pattern than mice exposed to Tet throughout the entire period. Moreover, 30% of these mice (three mice) survived through day 50. We conclude from these findings that BCR gene expression strongly inhibits the oncogenic effects of Bcr-Abl in NOD/scid mice, yielding healthy mice in most cases.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
leukemia  IMP 11038780 RGD 
leukemia  ISOBCR (Homo sapiens)11038780; 11038780 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Bcr  (BCR activator of RhoGEF and GTPase)

Genes (Mus musculus)
Bcr  (BCR activator of RhoGEF and GTPase)

Genes (Homo sapiens)
BCR  (BCR activator of RhoGEF and GTPase)


Additional Information