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Myeloid Neoplasms
Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis
Veronica Caraffini,1 Olivia Geiger,1 Angelika Rosenberger,1 Stefan Hatzl,1 Bianca Perfler,1 Johannes L. Berg,1 Clarice Lim,2 Herbert Strobl,2
Karl Kashofer,3 Silvia Schauer,3 Christine Beham-Schmid,3 Gerald Hoefler,3 Klaus Geissler,4,5 Franz Quehenberger,6 Walter Kolch,7 Dimitris Athineos,8 Karen Blyth,8 Albert Wölfler,1 Heinz Sill1 and Armin Zebisch1,9
1Division of Hematology, Medical University of Graz, Graz, Austria; 2Otto Loewi Research Center, Immunology and Pathophysiology, Medical University of Graz, Graz, Austria; 3Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria; 45th Medical Department with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria; 5Sigmund Freud University, Vienna, Austria; 6Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 7Systems Biology Ireland and Conway Institute, University College Dublin, Dublin, Ireland; 8Cancer Research UK Beatson Institute, Glasgow, UK and 9Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
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 com- mitment 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 fac- tor. We further show that RKIP is of relevance for RAS-driven myelomono- cytic 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 rele- vance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with RAS-signal- ing mutations. Taken together, these data establish RKIP as novel player in RAS-driven myeloid leukemogenesis.
Introduction
Activating RAS-signaling mutations comprise sequence variants within the RAS oncogenes themselves, but also can affect upstream activators and regulators of RAS- signaling cascades. Among others, these include CBL, PTPN11, NF1 as well as a wide range of receptor tyrosine kinases with relevance for physiological and malignant
Ferrata Storti Foundation
Haematologica 2018 Volume 105(2)375-386
Correspondence:
ARMIN ZEBISCH
armin.zebisch@medunigraz.at
Received: October 21, 2018. Accepted: May 15, 2019. Pre-published: May 16, 2019.
doi:10.3324/haematol.2018.209650
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/375
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