Targeting RAS Signaling Pathways in Juvenile Myelomonocytic Leukemia

Christian      Flotho; Christian      Kratz; Charlotte   M.   Niemeyer

Abstract

The RAS proteins function as fundamental signaling switches that control normal cell growth and differentiation. Deregulated activation of RAS-dependent signaling pathways constitutes a potent mechanism of malignant cell transformation. Juvenile myelomonocytic leukemia (JMML) is a rapidly fatal myeloproliferative disorder of early childhood for which no effective treatment other than hematopoietic stem cell transplantation is currently available. Many aspects of JMML pathobiology are linked to deregulated RAS signaling. Hence, targeting RAS or its interactors on a molecular level is a promising strategy in the development of novel rational therapies for this menacing disease. Here we give an overview of current concepts on the pathogenesis of JMML, present important aspects of cellular RAS biology that can be exploited for pharmacologic manipulation, and discuss mouse models that have greatly advanced our understanding of the role RAS plays in JMML. In addition, we review recent approaches to develop agents that interfere with the RAS network at the level of the granulocyte-macrophage colony-stimulating factor receptor, posttranslational RAS processing (prenylation and endoprotease cleavage), RAF serine/threonine kinase, MEK mitogen-activated protein kinase, and target of rapamycin activity. Preclinical and clinical data of these pharmaceuticals in JMML and other myeloid malignancies is discussed.

Keywords: Leukemia, myeloid, JMML, targeted therapy, RAS, RAF, MEK, TOR