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Selective treatment of mixed-lineage leukemia leukemic stem cells through targeting glycogen synthase kinase 3 and the canonical Wnt/-catenin pathway

Fung, Tsz K.a,*; Gandillet, Arnauda,b,*; So, Chi W.E.a

Current Opinion in Hematology: July 2012 - Volume 19 - Issue 4 - p 280–286
doi: 10.1097/MOH.0b013e3283545615
HEMATOPOIESIS: Edited by Hal E. Broxmeyer

Purpose of review: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs).

Recent findings: Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of β-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development.

Summary: On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.

aLeukaemia and Stem Cell Biology Group, Department of Heamatological Medicine, The Rayne Institute, King's College London

bCancer Research UK Haematopoietic Stem Cell Group, London Research Institute, London, UK

*These authors contributed equally to this work.

Correspondence to Chi W.E. So, Leukaemia and Stem Cell Biology Group, The Rayne Institute, King's College London, 123 Coldharbour Lane, London SE5 9NU, UK. Tel: +44 20 7848 5888; e-mail: eric.so@kcl.ac.uk/www.ericso.org

© 2012 Lippincott Williams & Wilkins, Inc.