Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice

Abstract

Pharmacological inactivation of cancer genes or products is being used as a strategy for therapy in oncology. To investigate the potential role of BCR-ABLp190 cessation in leukaemia development, we generated mice carrying a tetracycline-repressible BCR-ABLp190 transgene. These mice were morphologically normal at birth, and developed leukaemias. Disease was characterized by the presence of B-cell blasts co-expressing myeloid markers, reminiscent of the human counterpart. BCR-ABLp190 activation can initiate leukaemia in both young and adult mice. Transitory expression of BCR-ABLp190 is enough to develop leukaemia. Suppression of the BCR-ABLp190 transgene in leukaemic CombitTA-p190 mice did not rescue the malignant phenotype, indicating that BCRABLp190 is not required to maintain the disease in mice. Similar results were obtained by inactivation of BCRABLp190 with STI571 (Gleevec; Novartis, East Hanover, NJ, USA) in leukaemic CombitTA-p190 mice. However, gradual suppression of BCR-ABLp190 in leukaemic CombitTA-p190 mice identified a minimum level of BCR-ABLp190 expression necessary to revert the specific block in B-cell differentiation in the leukaemic cells. Overall, the findings indicate that BCR-ABLp190 appears to cause epigenetic and/or genetic changes in tumourmaintaining cells that render them insensitive to BCRABLp190 inactivation.

The theoretical basis of cancer‐stem‐cell‐based therapeutics of cancer: can it be put into practice?

“…This is supported by experiments with animal models in which expression of BCR-ABLp190 (the oncogene responsible of Ph þ B-ALL) is driven by a tetracycline-inducible promoter. (43) In this system, suppression of the oncogene after this has already been active does not suppress the leukaemia, indicating that the oncogene is necessary for the initiation of the tumour, but not for its maintenance. Similarly, although treatment of BCR-ABLp210 þ chronic myelogenous leukemia patients with the specific inhibitor imatinib mesylate (Gleevec), kills more differentiated progeny and greatly reduces tumour burden, it is unable to cure the disease because Ph þ stem cells are insensitive to the treatment and regenerate the disease.…”

The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia

“…Boff-p210 is a murine interleukin 3 (IL3) -independent cell line derived from the hematopoietic cell line Baf/3 [38] that expresses BCR/ABL as a tetracycline-regulated transgene ( BCR/ABL expression is constitutive in the absence of tetracycline or doxycycline) [52–54]. Boff-p210 was maintained in Dulbecco's Modified Eagle's Medium (DMEM) (Life Technologies) supplemented with 10% fetal bovine serum (FBS) and 1% of penicillin/streptomycin (Life Technologies) in 5% CO 2 at 37°C.…”

Genetically engineered mouse models of human B-cell precursor leukemias

“…In other study, using the pB-ALL-associated BCR-ABLp190 form in a tetracycline controllable system, it has been shown that inactivation of the oncogene expression, however, does not stop tumor growth once initiated. 33 These inducible transgenic mice suffer from pB-ALL that cannot be rescued by oncogene inactivation or by Imatinib treatment, similarly to what happens in humans, suggesting that the induction of tumorigenesis does not only depends on the oncogene, but also largely on its pattern of expression, and pointing toward a setting in which the oncogene imposes a leukemic stem cell-specific epigenetic context in which oncogene inactivation cannot lead anymore to a reversion of the phenotype. 33 The discrepancies between the results arising from models that are not so dissimilar in their design also highlight and exemplify the importance of defining stringent phenotypic requirements before concluding that a given mouse model actually recapitulates one of several aspects of the pathology in humans.…”