Bcr/Abl associated leukemogenesis in bcr null mutant mice

Voncken, Jan Willem; Kaartinen, Vesa; Groffen, John; Heisterkamp, Nora

doi:10.1038/sj.onc.1201730

Cited by 13 publications

(11 citation statements)

References 16 publications

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“…Our model would appear to con¯ict with the recent data published by the Groen group (Voncken et al, 1995(Voncken et al, , 1998. The most recent ®ndings (Voncken et al, 1998) indicate that Bcr has no signi®cant role in leukemias induced in BCR-ABL transgenic mice.…”

Section: Discussionsupporting

confidence: 44%

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Bcr: a negative regulator of the Bcr-Abl oncoprotein

Dai

et al. 1999

Oncogene

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Chronic myelogenous leukemia is typically characterized by the presence of the Philadelphia chromosome (Ph) in which 5' portions of the BCR gene are fused to a large portion of the ABL gene. Our studies and those of others indicate that Bcr sequences within the Bcr-Abl oncoprotein are critically involved in activating the Abl tyrosine kinase and actively participate in the oncogenic response, which is generated by the Bcr-Abl oncoprotein. We investigated the role of the Bcr protein in the oncogenic eects of Bcr-Abl. Reduction of the level of the Bcr protein by incubating cells with a 3' BCR anti-sense oligodeoxynucleotide increased the growth rate and survival of hematopoietic cell lines expressing Bcr-Abl. Also, enforced expression of Bcr in Bcr-Abl cell lines strongly reduced transformation eciency. Induction of Bcr expression drastically reduced the phosphotyrosine content of Bcr-Abl in Rat-1 ®broblasts transformed by P185 BCR-ABL and in hematopoietic cells expressing P210 Bcr-Abl within days following induction of Bcr. Rat-1/P185 cells maintained for three weeks after Bcr induction had dramatically reduced amounts of phosphotyrosine proteins compared to cells in which Bcr expression was repressed by the addition of Tet. In contrast Bcr expression did not decrease the phosphotyrosine content of either v-Src or activated Neu tyrosine kinase. Importantly, the phosphotyrosine content of total P160 BCR (induced plus endogenous) was strongly reduced by inducing expression of Bcr, indicating that the induced Bcr protein was not a target of the tyrosine kinase activity of Bcr-Abl but instead functioned as an inhibitor of Bcr-Abl. These results show that the Bcr protein can function as a negative regulator of Bcr-Abl, but that the inhibitory eects of Bcr are dependent on achieving an elevated level of Bcr expression relative to Bcr-Abl.

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Section: Discussionsupporting

confidence: 44%

“…The most recent ®ndings (Voncken et al, 1998) indicate that Bcr has no signi®cant role in leukemias induced in BCR-ABL transgenic mice. These experiments were performed by mating BCR knockout mice with BCR-ABL transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Bcr: a negative regulator of the Bcr-Abl oncoprotein

Dai

et al. 1999

Oncogene

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“…The ensuing progeny (P190 BCR/ABL transgenic, crkl+/ 7) was then intercrossed to obtain matched crkl7/7 and crkl+/+ P190 BCR/ABL genotypes. Previous experiments (Voncken et al, 1998) have shown that the speed with which leukemia develops in the P190 BCR/ ABL transgenic mice is markedly in¯uenced by the genetic background in which the transgene is expressed. Hence, we only used the F 1 generation of the P190 BCR/ABL transgenic, crkl+/7 intercrosses for this study.…”

Section: Leukemia/lymphoma Develops In P190 Bcr/abl Transgenics In Thmentioning

confidence: 99%

BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl

et al. 2002

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The Bcr/Abl fusion protein directly causes chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia. Multiple independent studies have implicated Crkl, a small adapter protein, in transduction of oncogenic signals of Bcr/Abl and Crkl tyrosine-phosphorylation is used as a diagnostic tool for Philadelphia-positive leukemia. To evaluate the contribution of Crkl to this type of leukemia, we generated mutant mice that lack Crkl expression. We found that the overall survival of P190 BCR/ABL crkl7/7 mice was comparable to that of genetically matched P190 BCR/ABL crkl +/+ mice. Both genotypes developed lymphoid lineage leukemia/lymphoma. Western blot analysis of 7/7 and +/+ lymphomas showed that the related Crk protein was tyrosine phosphorylated and could be found complexed with Bcr ± Abl P190. These data indicate that possible therapeutic approaches that target Crkl may be complicated by the presence of pathways that compensate for lack of Crkl function.

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“…It is also simple to breed a BCR/ABL transgene into different genetic backgrounds to test the role of other genes in leukemogenesis. This has allowed the demonstration that lymphoid leukemogenesis by p190 BCR/ABL does not require the normal bcr gene product [26], whereas the tec-p210 transgenic mice rapidly develop T lymphomas rather than myeloproliferative disease in a p53 heterozygous background [27]. Although it is difficult, transgenic mice can be used to test the requirement of different functional domains of Bcr/Abl for leukemogenesis, and a recent study demonstrated that the C-terminal actin-binding domain was required for efficient development of lymphoid leukemia in mice [28].…”

Section: Applications Of Bcr/abl Transgenic Micementioning

confidence: 99%

Models of chronic myeloid leukemia

Etten

2001

Curr Oncol Rep

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Bcr/Abl associated leukemogenesis in bcr null mutant mice

Cited by 13 publications

References 16 publications

Bcr: a negative regulator of the Bcr-Abl oncoprotein

Bcr: a negative regulator of the Bcr-Abl oncoprotein

BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl

Models of chronic myeloid leukemia

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