Aberrant Activation of the Hedgehog Signaling Pathway in Malignant Hematological Neoplasms

The hedgehog (HH) signaling pathway is a highly regulated signaling pathway that is important not only for embryonic development, tissue patterning, and organogenesis but also for tissue repair and the maintenance of stem cells in adult tissues. In the adult hematopoietic system, HH signaling regulates intrathytmic T-cell development, and it is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. HH signaling is required for primitive hematopoiesis; however, conflicting data have been reported regarding the role of the HH pathway in adult hematopoiesis. Inappropriate activation of the HH signaling pathway occurs in several human cancers, including hematological neoplasms. Emerging data demonstrate abnormal HH pathway activation in chronic lymphocytic leukemia/small lymphocytic lymphoma, plasma cell myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, ALK-positive anaplastic large cell lymphoma, chronic myelogenous leukemia, and acute leukemias. In these neoplasms, HH signaling promotes proliferation and survival, contributes to the maintenance of cancer stem cells, and enhances tolerance or resistance to chemotherapeutic agents. Here, we review current understanding of HH signaling, its role in the pathobiology of hematological malignancies, and its potential as a therapeutic target to treat malignant hematological neoplasms. (Am J Patbol 2012, 180:2-11; DOI: 10.1016/j.ajpath.2011.09.009)