Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development

Abstract

A strict balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is required in order to maintain homeostasis, as well as to efficiently respond to injury and infections. Numbers and fate decisions made by progenitors derived from HSC must also be carefully regulated to sustain large scale production of blood cells. The complex Wnt family of molecules generally is thought to be important to these processes, delivering critical signals to HSC and progenitors as they reside in specialized niches. Wnt proteins have also been extensively studied in connection with malignancies and are causatively involved in development of several types of leukemias. However, studies with experimental animal models have produced contradictory findings regarding the importance of Wnt signals for normal hematopoiesis and lymphopoiesis. Here we will argue that dose dependency of signaling via particular Wnt pathways accounts for much, if not all of this controversy. We conclude that there seems little doubt that Wnt proteins are required to sustain normal hematopoiesis, but are likely to be presented in carefully controlled gradients in a tissue specific fashion.

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

“…This is achieved by down-regulation of key members in the destruction complex (APC/APC2). In contrast to TGFb, Wnt signaling is a positive regulator of self-renewal in HSCs and for megakaryopoiesis (Luis et al 2012;Macaulay et al 2013). When Wnt signaling is modestly enhanced, HSCs reconstitute better.…”

“…Wnt3a, one of 19 distinct Wnt ligands, has been reported to induce Wnt signaling in the hematopoietic system (Luis et al 2012). Similar to miR-99a;125b-2, supplementation with Wnt3a during megakaryocytic differentiation increased the total number of cells (Supplemental Fig.…”

Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

“…While there are conflicting data on the role of WNT signaling in normal hematopoietic stem cell self-renewal, mouse models have demonstrated that β-catenin is critical for AML stem cell self-renewal. [2][3][4] These data, combined with the clinical observation that increased canonical WNT signaling in AML blasts at diagnosis is associated with decreased rates of relapse-free and overall survival, suggested a potential clinical benefit for WNT suppression. 5,6 While this approach has shown promise in the treatment of AML, haematologica 2015; 100:e49 questions remain as to which subtypes of AML will benefit.…”

β-Catenin induces T-cell transformation by promoting genomic instability

“…In normal development Wnt activity is shortlived and expression of Wnt target genes oscillates, suggesting that Wnt activity is controlled by inherent negative feedback loops (8). Uncontrolled activation of the central effector of Wnt signaling, β-catenin, has been causatively linked to genome instability in multiple cancers, including hematopoietic malignancies (9)(10)(11)(12). However, how uncontrolled β-catenin promotes genomic instability in these malignancies is unknown.…”