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

It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphi a 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 expr ession on Bcr-Abl oncogenic effects in a more physiological system, we test ed 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 pl aced under the control of a tetracycline (Tet) repression system with a cyt omegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kin ase activity, yielding predominantly phosphoserine Bcr, despite the presenc e of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endoge nous Bcr was predominantly in the phosphotyrosine form because of phosphory lation by Bcr-Abl, which we previously have shown suppresses Bcr serine/thr eonine kinase activity, Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or termin al illness in 100% of the mice within 35 days after injection. These mice h ad a severe wasting syndrome characterized by atrophy of bone marrow hemato poiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic sple ens 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 inte rest, mire that were fed Tet for 19 days to initiate the disease syndrome a nd then released from the BCR transcriptional block had a significantly bet ter survival pattern than mice exposed to Tet throughout the entire period. Moreover, 30% of these mice (three mice) survived through day 50, We concl ude from these findings that BCR gene expression strongly inhibits the onco genic effects of Bcr-Abl in NOD/scid mice, yielding healthy mice in most ca ses.