Myelodysplastic Syndrome Caused By Activating Kras Mutation in the Non-Hematopoietic Bone Marrow Microenvironment
Autor: | Robert Zeiser, Justus Duyster, Cornelius Miething, Tilman Brummer, Lena Osswald |
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Rok vydání: | 2015 |
Předmět: | |
Zdroj: | Blood. 126:359-359 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Oncogenic Ras mutations occur frequently in myelodysplastic and myeloproliferative syndromes as juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) as well as in acute myeloid leukemia. However in these reports the mutations were in the hematopoietic cells. Here, we show that an activating mutation of Kras in the non-hematopoietic system leads to hematologic disorder resembling human myelodysplastic syndrome (MDS). Rosa26CreERT2;LSL-KrasG12D mice (CD45.2) were lethally irradiated and transplanted with wild-type bone marrow (CD45.1). After control of engraftment efficiency (above 99.6%), the mice were treated with Tamoxifen to induce the expression of KrasG12D in non-hematopoietic cells. 6-8 weeks after Tamoxifen treatment, the mice developed anemia, leukocytopenia and thrombocytopenia and had a highly increased percentage of myeloid cells in peripheral blood, spleen and bone marrow. FACS-analysis confirmed that these cells were donor-derived and therefore of wild-type origin. The frequency of immature myeloid progenitors (CD11b+ c-kit+) was increased in bone marrow of Rosa26CreERT2;LSL-KrasG12D mice compared to littermate controls suggesting a disturbed differentiation. Morphological analysis of blood smears and bone marrow revealed a high number of dysplastic hypersegmented neutrophils as well as the occurrence of myeloid blasts. Additionally, a significant decrease of B-lymphocytes was observed in the bone marrow of KrasG12D recipient mice which has also been described in human MDS. Osteoblasts have been shown to contribute to B-cell lymphopoiesis which implicates that decreased B-cell lymphopoiesis in this study may be a result of oncogenic Kras expression in osteoblasts. All these data indicate that a single mutation in the hematopoietic microenvironment can initiate a severe hematologic disorder. The expression of oncogenic Kras in bone marrow stroma cells leads to a shift to myeloid differentiation, severe anemia and thrombocytopenia as well as reduced B-cell counts recapitulating main signs of human myelodysplastic syndrome. Disclosures No relevant conflicts of interest to declare. |
Databáze: | OpenAIRE |
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