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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000058
LYMPHOID BIOLOGY AND DISEASES: Edited by Ari M. Melnick

The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia

Tremblay, Cedric S.; Curtis, David J.

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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.

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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