An Mb1-Cre-driven oncogenic Kras mutation results in a mouse model of T-acute lymphoblastic leukemia/lymphoma with short latency and high penetrance

Junco, Jacob J.; Chen, Taylor; Rashid, Raushan; Terrell, Maci; Gant, Vincent U.; Miller, Michelle; Rau, Rachel E.; Lacorazza, H. Daniel; Rabin, Karen R.

doi:10.1038/s41375-020-01036-w

Cited by 3 publications

(2 citation statements)

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“…Of note, NOTCH1 L1601P-∆P Klf4 ∆/∆ bone marrow cells were collected one month after transplantation to perform the cell viability assay in parallel and therefore may contain a mixture of leukemic and polyclonal expansions with activated NOTCH1 [ 9 ]. Second, T-ALL cells from the novel Kras LSL-G12D/+ .Mb1 Cre/+ mouse model that spontaneously develops T-ALL were tested against 5Z7O [ 32 ]. Thymic cells collected from mice with full-blown T-ALL showed significantly increased sensitivity to 5Z7O compared to thymic cells from healthy age-matched control mice ( Figure 5B ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Chen

Junco

et al. 2021

Oncotarget

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric leukemia with a worse prognosis than most frequent B-cell ALL due to a high incidence of treatment failures and relapse. Our previous work showed that loss of the pioneer factor KLF4 in a NOTCH1-induced T-ALL mouse model accelerated the development of leukemia through expansion of leukemia-initiating cells and activation of the MAP2K7 pathway. Similarly, epigenetic silencing of the KLF4 gene in children with T-ALL was associated with MAP2K7 activation. Here, we showed the small molecule 5Z-7-oxozeaenol (5Z7O) induces dose-dependent cytotoxicity in a panel of T-ALL cell lines mainly through inhibition of the MAP2K7-JNK pathway, which further validates MAP2K7 as a therapeutic target. Mechanistically, 5Z7O-mediated apoptosis was caused by the downregulation of regulators of the G2/M checkpoint and the inhibition of survival pathways. The anti-leukemic capacity of 5Z7O was evaluated using leukemic cells from two mouse models of T-ALL and patient-derived xenograft cells generated using lymphoblasts from pediatric T-ALL patients. Finally, a combination of 5Z7O with dexamethasone, a drug used in frontline therapy, showed synergistic induction of cytotoxicity. In sum, we report here that MAP2K7 inhibition thwarts survival mechanisms in T-ALL cells and warrants future pre-clinical studies for high-risk and relapsed patients.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Chen

Junco

et al. 2021

Oncotarget

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“…Thus, this pooling of bone marrow resulted in a ‘solitary sample’ with activated Kras G12D , and explains the difference between the BMT mice (where 100% developed T-ALL) and the KC mice (where 30% die by age 9 months). Similar to other Kras -mutant leukemia models, 11, 12 BMT mice receiving AiKC bone marrow were deceased within 3-4 months of transplantation. This reflects the aggressiveness of Kras -mutant leukemia, where onset of Kras -mutation in the hematopoietic cells causes rapid demise.…”

Section: Discussionmentioning

confidence: 99%

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-Kras^G12D/+) mice

Walcheck

Nukaya

Ranheim

et al. 2022

Preprint

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BackgroundPdx1 expression in pancreatic lineage cells underlies the utility of the KC mouse model (Pdx1-Cre; LSL-KrasG12D/+) for understanding how KrasG12D-mutation drives formation of pancreas cancer precursor lesions and carcinoma. The highly utilized KC model has a reported mortality rate of about 30%, which has been attributed to pancreas cancer, despite lack of substantive evidence. This study describes a novel cause of the early deaths, in which KC mice develop Kras-driven T-cell acute lymphoblastic leukemia (T-ALL).MethodsKC mice and control mice underwent histopathologic examination including thymus, liver, spleen, bone marrow and pancreas, and immunohistochemistry (IHC) was used to confirm leukemia development. A reporter strain (Ai14) was used to identify location of Pdx1-Cre expression and concomitant mutant-Kras activation, which was confirmed using flow cytometry, IHC, immunofluorescence, mRNA analysis, and bone marrow transplant studies.ResultsPdx1 expression in the hematopoietic compartment of KC mice resulted in Cre-recombinase mediated excision of lox-stop and activation of mutant-Kras gene (KrasG12D/+) in the multipotent progenitor cells (MPP), and subsequent development of Kras-mutant T-ALL creating thymic tumors in a subset of mice. Overall, 20% (5/25) of KC mice developed a large thymic tumor due to T-ALL by 9 months of age. Moreover, through isolation and transplantation of pooled bone marrow from KC mice into CD45 congenic mice, 100% of recipient mice were found to develop T-ALL. These results further confirm mutant-Kras expression in the hematologic compartment is driving the development of T-ALL in the KC mouse model.ConclusionsThese results are an essential consideration for investigators while utilizing this model in pancreas cancer studies, particularly when evaluating factors that may coincidentally enhance the formation of KrasG12D-driven T-ALL (e.g. transcription factors impacting hematopoietic cells). Finally, the lower penetrance of T-ALL development in KC mice (compared to existing leukemia models) suggest that the KC mouse could be considered as an alternative research model to evaluate onset and factors that exacerbate development of T-ALL.

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Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre; LSL-Kras^G12D/+) mice

Walcheck

Nukaya

Ranheim

et al. 2023

Leukemia & Lymphoma

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An Mb1-Cre-driven oncogenic Kras mutation results in a mouse model of T-acute lymphoblastic leukemia/lymphoma with short latency and high penetrance

Cited by 3 publications

References 15 publications

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-Kras^G12D/+) mice

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre; LSL-Kras^G12D/+) mice

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An Mb1-Cre-driven oncogenic Kras mutation results in a mouse model of T-acute lymphoblastic leukemia/lymphoma with short latency and high penetrance

Cited by 3 publications

References 15 publications

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-KrasG12D/+) mice

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre; LSL-KrasG12D/+) mice

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Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-Kras^G12D/+) mice

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre; LSL-Kras^G12D/+) mice