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

A Staffas, C Karlsson, M Persson, L Palmqvist… - Leukemia, 2015 - nature.com
A Staffas, C Karlsson, M Persson, L Palmqvist, MO Bergo
Leukemia, 2015nature.com
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 …
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.
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