Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice

Abstract

The role of hyperactive RAS signaling is well established in myeloid malignancies but less clear in T-cell malignancies. The Kras2(LSL)Mx1-Cre (KM) mouse model expresses endogenous KRAS(G12D) in hematopoietic cells and is widely used to study mechanisms and treatment of myeloproliferative neoplasms (MPN). The model displays an intriguing shift from MPN to acute T-cell leukemia (T-ALL) after transplantation to wild-type mice, but the mechanisms underlying this lineage shift is unknown. Here, we show that KRAS(G12D) increases proliferation of both myeloid and T-cell progenitors, but whereas myeloid cells differentiate, T-cell differentiation is inhibited at early stages. Secondary mutations in the expanded pool of T-cell progenitors accompany T-ALL development, and our results indicate that the shift from myeloid to T-lymphoid malignancy after transplantation is explained by the increased likelihood for secondary mutations when the tumor lifespan is increased. We demonstrate that tumor lifespan increases after transplantation because primary KM mice die rapidly, not from MPN, but from KRAS(G12D) expression in nonhematopoietic cells, which causes intestinal bleeding and severe anemia. We also identify loss of the wild-type KRAS allele as a secondary mutation in all T-ALL cells and provide evidence that wild-type KRAS acts as a tumor suppressor in the T-cell lineage in mice.

Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis

“…Our results are consistent with a human study of early T-cell precursor ALL, which identified KRAS G12D/ − mutations in patient tumor cells (23). However, our result is contradictory to a prior study reporting that loss of WT Kras expression in oncogenic Kras -induced T-ALL is due to uniparental disomy of oncogenic Kras allele (24). This difference might be due to the small sample size included in both studies, which could be biased by the pre-disposed genetic alterations in the donor cells.…”

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

“…All Flt3Cre + Kras G12D mice succumbed to a myeloid disease that could be recapitulated following FL transplantation. This is in contrast to existing Kras G12D models, whose MPN is exacerbated by nonhematopoietic oncogene expression and by the unpredictable coemergence of T-ALL (15)(16)(17)(18)(19)(20).…”

“…The Mx1Cre Kras G12D mouse was the first conditional animal model of JMML and continues to be studied extensively (12,13). However, these mice succumb with MPN that can be exacerbated by T cell leukemia/lymphoma (T-ALL) and that is confounded by nonhematopoietic Kras G12D expression (14)(15)(16)(17)(18). While the use of inducible Mx1Cre serves to limit oncogene expression until after birth, in utero Kras G12D expression owing to spontaneous Mx1Cre activity was not assessed in this model.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…The wild-type KRAS allele may serve to counter the function of the oncogenic KRAS allele (Zhang et al 2001;Staffas et al 2015). This concept derives from LOH of the wild-type KRAS allele in lung cancer and PDAC with oncogenic KRAS mutation (Li et al 2003;Qiu et al 2011) and is consistent with the selective amplification of the oncogenic Kras allele in the GEMM of PDAC (Bardeesy et al 2006a).…”