Expression of BCR/ABL p210 from a Knockin Allele Enhances Bone Marrow Engraftment without Inducing Neoplasia

Abstract

Chronic myeloid leukemia (CML) and some acute lymphoblastic leukemias are characterized by the t(9;22) that encodes the BCR/ABL oncogene. Multiple mouse models of CML express BCR/ABL at high levels from non-Bcr promoters, resulting in the development of leukemias. In contrast, a significant fraction of healthy humans have been found to have BCR/ABL positive hematopoietic cells. To bridge the gap between the information derived from current mouse models and the non-leukemic humans with the BCR/ABL oncogene, we generated a knockin model with BCR/ABL p210 expressed from the Bcr locus. Unlike previous models, expression of BCR/ABL from the knockin allele did not induce leukemia. BCR/ABL mutant cells did exhibit favorable bone marrow engraftment compared to wild-type cells. These data suggest BCR/ABL expression alone is insufficient to induce disease. This new model allows for inducible spatial and temporal control of BCR/ABL expression for analysis of early steps in the pathogenesis of BCR/ABL-expressing leukemias.

Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

“…These results suggest that Vav1-iCre;Brca1 F22-24/+ HSCs do in fact exhibit a reduced self-renewal capacity as compared to wild-type HSCs. Although single Vav1-iCre transgenic mice were not used as controls in this cohort, CBC abnormalities or defects in primary or secondary reconstitution by bone marrow cells from Vav1-iCre mice in the same pure C57/BL6 background have not been observed previously (Foley et al, 2013). These observations in mice are consistent with greater chemotoxicity in humans with BRCA1 mutations and suggest that heterozygosity for a loss-of-function mutation in Brca1 can impair the ability to regenerate hematopoiesis after one or more cycles of chemotherapy (Figure 1g).…”

“…Flow cytometric analysis of specific hematopoietic progenitors was performed as previously described (Foley et al, 2013; Signer et al, 2014). Complete blood cell count analysis was performed on peripheral blood using the Hemavet 950 with MULTI-TROL Mouse as an equilibration control (Drew Scientific).…”

The chronic myeloid leukemia stem cell: stemming the tide of persistence

“…However, issues with BCR-ABL1 copy number, high oncogene expression and/or secondary mutations arising by retroviral or transgene insertional mutagenesis or genomic instability could theoretically contribute to leukaemogenesis. In a recent knock-in model, a single copy of BCR-ABL1 expressed from the endogenous BCR locus was able to confer enhanced BM engraftment, however this model was unable to induce leukaemia 10 .…”

Somatic Engineering of Oncogenic Chromosomal Rearrangements: A Perspective

“…Initially applied to model the MLL-AF9 translocation frequently observed in acute myelogenous leukemia (25), this strategy has been used over the past 20 years to successfully generate mouse of models of hematologic and solid tumors (for example (26, 27)). An important additional benefit of this approach is the potential to generate conditional, Cre-inducible, knock-in alleles, for example by placing a transcriptional stop cassette flanked by loxP sites just downstream of the promoter.…”