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

Tremblay, Cedric S.; Curtis, David J.

Current Opinion in Hematology: July 2014 - Volume 21 - Issue 4 - p 320–325
doi: 10.1097/MOH.0000000000000058
LYMPHOID BIOLOGY AND DISEASES: Edited by Ari M. Melnick

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.

Australian Centre for Blood Diseases, Department of Clinical Haematology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia

Correspondence to David J. Curtis, Australian Centre for Blood Diseases, 75 Commercial Road, AMREP Building level 1, Melbourne, VC 3004, Australia. Tel: +61 3 9903 0225; e-mail: david.curtis@monash.edu

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins