A new mouse model of Kras mutation-driven T-ALL

Childhood ALL frequently has mutations activating the Ras pathway, which are associated with poorer outcomes and resistance to chemotherapy in both B-cell ALL and T-cell ALL. The mutated Ras protein is also difficult to target. To potentially uncover mechanisms of leukemia formation and new targets for treatment, we set out to develop a novel mouse model of Ras-mutation-driven ALL. We used Cre-mediated recombination to activate Kras^G12D, a common mutation driving hyperactive Ras signaling. Since we are interested in both B-cell ALL and T-cell ALL, we chose to activate Kras^G12D with the Mb1-Cre mouse model, which expresses Cre in nearly all B cells, but also in a small percentage of early T cells. Surprisingly, the resulting mice (Kras^LSL-G12D/+.Mb1^Cre/+) all developed T-cell ALL or T-cell lymphoma, and none developed B cell disease. These mice demonstrated an aberrant combination of T-cell markers and had enlarged spleens and thymuses infiltrated with large diseased cells. Mice also died with a predictable and short latency (see accompanying figure). The disease was also readily transplantable, and the cells were sensitive to standard chemotherapies.

These Kras^LSL-G12D/+.Mb1^Cre/+ mice may provide a relevant pre-clinical model of T-cell ALL. They develop disease with a very short and predictable latency, making them well-suited for testing novel therapies. The resulting disease shows overexpression of CD44, which is associated with T-cell ALL relapse. Also, RAS-mutated T-cell ALL was more recently classified as a high-risk subtype, and requires more comprehensive pre-clinical evaluation. Importantly, our novel mouse model requires no immunosuppression or transplantation. This makes them ideally suited for studies of the earliest stages of leukemia formation, including analyses of pre-leukemic clones. These studies may involve determining when and how secondary mutations are acquired, and how they may affect disease progression and response to therapy. These mice are also fully immunocompetent, and making them more useful for analyses of chemoprotective interactions between T-cell ALL and immune cells, or for more comprehensive immunotherapy applications. Overall, this novel mouse model could yield critical insights to develop more effective therapies against T-cell leukemias and lymphomas. Our manuscript can be accessed here:  https://rdcu.be/b65kg.