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Wild-type KRAS inhibits oncogenic KRAS-induced T-all in mice.

Artikel i vetenskaplig tidskrift
Författare Anna Staffas
Christin Karlsson
Marta Persson
Lars Palmqvist
Martin Bergö
Publicerad i Leukemia
Volym 29
Sidor 1032–1040
ISSN 1476-5551
Publiceringsår 2015
Publicerad vid Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin
Sahlgrenska Cancer Center
Sidor 1032–1040
Språk en
Länkar dx.doi.org/10.1038/leu.2014.315
Ämnesord Leukemi, KRAS, T-ALL
Ämneskategorier Molekylär medicin

Sammanfattning

The role of hyperactive RAS signaling is well established in myeloid malignancies but less clear in T-cell malignancies. The Kras2LSLMx1-Cre (KM) mouse model expresses endogenous KRASG12D 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 KRASG12D 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 life-span is increased. We demonstrate that tumor life span increases after transplantation because primary KM mice die rapidly, not from MPN, but from KRASG12D 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.Leukemia accepted article preview online, 05 November 2014. doi:10.1038/leu.2014.315.

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