Wnt Signaling in Normal and Malignant Hematopoiesis

Abstract

One of the most remarkable characteristics of stem cells is their ability to perpetuate themselves through self-renewal while concomitantly generating differentiated cells. In the hematopoietic system, stem cells balance these mechanisms to maintain steady-state hematopoiesis for the lifetime of the organism, and to effectively regenerate the system following injury. Defects in the proper control of self-renewal and differentiation can be potentially devastating and contribute to the development of malignancies. In this review, we trace the emerging role of Wnt signaling as a critical regulator of distinct aspects of self-renewal and differentiation, its contribution to the maintenance of homeostasis and regeneration, and how the pathway can be hijacked to promote leukemia development. A better understanding of these processes could pave the way to enhancing recovery after injury and to developing better therapeutic approaches for hematologic malignancies.

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…[45][46][47] In several hematological malignancies, including MCLs, Wnt signaling enhances cell viability, whereas its inhibition reduces it. 5,15,17,18,20 We therefore questioned whether ZEB1 determines enhanced cell viability in MCL cells. As shown in Figure 4a, knockdown of ZEB1 resulted in a partial decrease of MCL basal cell viability that was similar to that obtained by interference of b-catenin.…”

“…At the nucleus, b-catenin complexes with TCF-LEF transcription factors to transcriptionally activate Wnt target genes. 20,26 In solid tumors, b-catenin colocalizes with the transcription factor ZEB1 in the nuclei of undifferentiated cancer cells at the invasive front. [27][28][29][30][31] Depending on the target gene, ZEB1 could function as either a transcriptional repressor or an activator through the recruitment of different cofactors.…”

“…1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common. 3,[5][6][7]21 Short-lived response and development of resistance to first-line immunochemotherapy are major challenges in MCL and new therapeutic strategies are being developed.…”

“…1,22,23 Constitutive Wnt signaling associates to increased cellular proliferation and higher resistance to apoptosis and chemotherapy in subsets of leukemias and lymphomas and established cell lines derived from them, including MCLs. 3,5,6,13,[15][16][17][18][19][20] In turn, inhibitors of Wnt pathway induce cytotoxicity in leukemia and lymphoma cells. 5,16,17 The characterization in MCLs of a subpopulation of stem-like cells retaining the capacity for tumor initiation could help explaining relapses and also offers new avenues in MCL treatment.…”

Ex vivo expansion of hematopoietic stem cells

“…Wnt signaling is involved in HSC regulation (reviewed in [59,123]), and Wnt signaling was reported to maintain HSC in a quiescent status in vivo [124]. The effects of Wnt signaling are dosage and context dependent: low Wnt doses result in expansion of HSCs, whereas high doses cause exhaustion [125].…”