Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

Abstract

Many acute lymphoblastic leukemias can be considered as malignant counterparts of cells in the various stages of normal lymphoid development in bone marrow and thymus. T-cell development in the thymus is an ordered and tightly controlled process. Two evolutionary conserved signaling pathways, which were first discovered in Drosophila, control the earliest steps of T-cell development. These are the Notch and Wnt-signaling routes, which both are deregulated in several types of leukemias. In this review we discuss both pathways, with respect to their signaling mechanisms, functions during T-cell development and their roles in development of leukemias, especially T-cell acute lymphoblastic leukemia.

Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype

“…For colon carcinoma, aberrations in Wnt signaling are causative factors that have also been proposed and are increasingly seen in hematological malignancies (reviewed in Refs. 32,33 ). Cluster 5 contains only 21 genes mainly involved in cell cycle regulation (14 of 21 genes), including TOP2A (3-fold upregulated in relapsed samples), encoding a DNA topoisomerase, that controls and alters the topologic states of DNA during transcription and is often upregulated in a wide variety of cancers; and KIF 11 (2.1-fold up), a kinesin family member 11 motor protein that controls spindle dynamics.…”

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…146 Cooperation between Wnt and Notch in HSCs has recently been suggested by Duncan et al 89 Furthermore, studies have demonstrated a role for Wnt and Notch in T-cell leukemias. 147 For example, Weng et al 148 could show that over 50% of human T-ALL patients have activating mutations in Notch1. Deregulated T-cell proliferation might result from suppression of p53 and/or activation of the NF-kB by Notch.…”

Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program

“…At least half of all human T-ALL carry activating mutations in the intracellular part of Notch1. 17,18 To develop into a T cell, Notch signaling is clearly indispensable, but the downstream mechanisms by which a Notch signal is translated into a T-cell program are still largely unclear. The best known Notch target genes are Hairy-Enhancer of Split (HES)1 and HES5 and Hes-related repressor protein (HERP).…”