Cedric S Tremblay1, David J Curtis. 1. Australian Centre for Blood Diseases, Department of Clinical Haematology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia.
Abstract
PURPOSE OF REVIEW: Recent genome sequencing studies have identified a broad spectrum of gene mutations in T-cell acute lymphoblastic leukemia (T-ALL). The purpose of this review is to outline the latest advances in our understanding of how these mutations contribute to the formation of T-ALL. RECENT FINDINGS: Aberrant expression of transcription factors that control hematopoiesis can induce an aberrant stem cell-like program in T-cell progenitors, allowing the emergence of an ancestral or preleukemic stem cell (pre-LSC). In contrast, gain-of-function mutations of genes involved in signaling pathways regulating T-cell development, such as NOTCH1, interleukin-7, KIT and FLT3, are insufficient per se to initiate T-ALL but promote pre-LSC growth independent of the thymic niche. Loss-of-function mutations of epigenetic regulators, such as DNMT3A, have been identified in T-ALL, but their role in leukemogenesis remains to be defined. SUMMARY: Relapse is associated with clonal evolution from a population of pre-LSCs that acquire the whole set of malignant mutations leading to a full-blown T-ALL. Understanding the genetic events that underpin the pre-LSC will be crucial for reducing the risk of relapse.
PURPOSE OF REVIEW: Recent genome sequencing studies have identified a broad spectrum of gene mutations in T-cell acute lymphoblastic leukemia (T-ALL). The purpose of this review is to outline the latest advances in our understanding of how these mutations contribute to the formation of T-ALL. RECENT FINDINGS: Aberrant expression of transcription factors that control hematopoiesis can induce an aberrant stem cell-like program in T-cell progenitors, allowing the emergence of an ancestral or preleukemic stem cell (pre-LSC). In contrast, gain-of-function mutations of genes involved in signaling pathways regulating T-cell development, such as NOTCH1, interleukin-7, KIT and FLT3, are insufficient per se to initiate T-ALL but promote pre-LSC growth independent of the thymic niche. Loss-of-function mutations of epigenetic regulators, such as DNMT3A, have been identified in T-ALL, but their role in leukemogenesis remains to be defined. SUMMARY: Relapse is associated with clonal evolution from a population of pre-LSCs that acquire the whole set of malignant mutations leading to a full-blown T-ALL. Understanding the genetic events that underpin the pre-LSC will be crucial for reducing the risk of relapse.
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Authors: Oxana Dobrovinskaya; Iván Delgado-Enciso; Laura Johanna Quintero-Castro; Carlos Best-Aguilera; Rocío Monserrat Rojas-Sotelo; Igor Pottosin Journal: Biomed Res Int Date: 2015-03-19 Impact factor: 3.411
Authors: Cedric S Tremblay; Sung Kai Chiu; Jesslyn Saw; Hannah McCalmont; Veronique Litalien; Jacqueline Boyle; Stefan E Sonderegger; Ngoc Chau; Kathryn Evans; Loretta Cerruti; Jessica M Salmon; Adam McCluskey; Richard B Lock; Phillip J Robinson; Stephen M Jane; David J Curtis Journal: Nat Commun Date: 2020-12-04 Impact factor: 14.919