Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Caraffini, V; Geiger, O; Rosenberger, A; Hatzl, S; Perfler, B; Berg, JL; Lim, C; Strobl, H; Kashofer, K; Schauer, S; Beham-Schmid, C; Hoefler, G; Geissler, K; Quehenberger, F; Kolch, W; Athineos, D; Blyth, K; Wölfler, A; Sill, H; Zebisch, A.
Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis.
Haematologica. 2020; 105(2):375-386
Doi: 10.3324/haematol.2018.209650
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- Führende Autor*innen der Med Uni Graz
- Caraffini Veronica
- Zebisch Armin
- Co-Autor*innen der Med Uni Graz
- Beham-Schmid Christine
- Geiger Olivia
- Hatzl Stefan
- Höfler Gerald
- Kashofer Karl
- Lim Clarice
- Perfler Bianca
- Quehenberger Franz
- Schauer Silvia
- Schlacher Angelika
- Sill Heinz
- Strobl Herbert
- Wölfler Albert
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- Abstract:
- RAS-signaling mutations induce the myelomonocytic differentiation and proliferation of hematopoietic stem and progenitor cells. Moreover, they are important players in the development of myeloid neoplasias. RAF kinase inhibitor protein (RKIP) is a negative regulator of RAS-signaling. As RKIP loss has recently been described in RAS-mutated myelomonocytic acute myeloid leukemia, we now aimed to analyze its role in myelomonocytic differentiation and RAS-driven leukemogenesis. Therefore, we initially analyzed RKIP expression during human and murine hematopoietic differentiation and observed that it is high in hematopoietic stem and progenitor cells and lymphoid cells but decreases in cells belonging to the myeloid lineage. By employing short hairpin RNA knockdown experiments in CD34+ umbilical cord blood cells and the undifferentiated acute myeloid leukemia cell line HL-60, we show that RKIP loss is indeed functionally involved in myelomonocytic lineage commitment and drives the myelomonocytic differentiation of hematopoietic stem and progenitor cells. These results could be confirmed in vivo, where Rkip deletion induced a myelomonocytic differentiation bias in mice by amplifying the effects of granulocyte macrophage-colony-stimulating factor. We further show that RKIP is of relevance for RAS-driven myelomonocytic leukemogenesis by demonstrating that Rkip deletion aggravates the development of a myeloproliferative disease in NrasG12D -mutated mice. Mechanistically, we demonstrate that RKIP loss increases the activity of the RAS-MAPK/ERK signaling module. Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with RAS-signaling mutations. Taken together, these data establish RKIP as novel player in RAS-driven myeloid leukemogenesis. Copyright© 2020 Ferrata Storti Foundation.