Targeting hedgehog in hematologic malignancy

Abstract

The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.

Abnormal Hedgehog pathway in myelodysplastic syndrome and its impact on patients' outcome

“…4 Kobune et al showed activation of Hh signaling in primary CD34 + blasts from AML 5 and, recently, these same authors reported the expression of Indian Hh (IHH) and Smoothed (SMO) in AML-and MDS-derived CD34 + cells. 6 Here, we characterize expression of central components of the Hh pathway in the bone marrow (BM) of MDS patients.…”

Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1–Positive Leukemia

“…[9][10][11][12]. Gli1 is a positive effector of signaling, Gli3 is predominantly a transcriptional inhibitor, and Gli2 can function in both roles (9)(10)(11)(12). Smo signals to a cytoplasmic complex that releases Gli1, which translocates to the nucleus where it activates the Hedgehog target genes (9,10,13).…”

“…The Hedgehog signaling pathway consists of 3 closely related ligands, Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh), that can each bind to the transmembrane protein Patched (PTCH; refs. [8][9][10]. Upon ligand binding, PTCH inhibition of the positive effector Smoothened (Smo) is released and leads to production of activating forms of glioma-associated oncoproteins 1-3 (Gli1-3; refs.…”

“…Upon ligand binding, PTCH inhibition of the positive effector Smoothened (Smo) is released and leads to production of activating forms of glioma-associated oncoproteins 1-3 (Gli1-3; refs. [9][10][11][12]. Gli1 is a positive effector of signaling, Gli3 is predominantly a transcriptional inhibitor, and Gli2 can function in both roles (9)(10)(11)(12).…”

Mulberry Anthocyanins Induce Leukemia WEHI-3 Cells Apoptosis, Autophagy, Differentiation and prolong leukemic mice survival

“…kinase, PTEN, p53) and self-renewal (Wnt, Hedgehog, Notch) pathways [2][3][4][5][6][7][8][9].Furthermore, the therapy is highly toxic and poorly tolerated, particularly by older patients. Therefore, the development of novel therapeutic agents and strategy is in an urgent need for improving outcomes in patients with AML.…”