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J Biol Chem. 2016 May 20;291(21):11148-60. doi: 10.1074/jbc.M116.717801. Epub 2016 Apr 4.

Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors.

Author information

1
From the State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China, ysy@cau.edu.cn.
2
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
3
From the State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
4
Department of Physics, The George Washington University, Washington, D. C. 20052, and.
5
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 hai-hui-xue@uiowa.edu.

Abstract

Hematopoietic and leukemic stem cells (HSCs and LSCs) have self-renewal ability to maintain normal hematopoiesis and leukemia propagation, respectively. Tcf1 and Lef1 transcription factors are expressed in HSCs, and targeting both factors modestly expanded the size of the HSC pool due to diminished HSC quiescence. Functional defects of Tcf1/Lef1-deficient HSCs in multi-lineage blood reconstitution was only evident under competitive conditions or when subjected to repeated regenerative stress. These are mechanistically due to direct positive regulation of Egr and Tcf3 by Tcf1 and Lef1, and significantly, forced expression of Egr1 in Tcf1/Lef1-deficient HSCs restored HSC quiescence. In a preclinical CML model, loss of Tcf1/Lef1 did not show strong impact on leukemia initiation and progression. However, when transplanted into secondary recipients, Tcf1/Lef1-deficient LSCs failed to propagate CML. By induced deletion of Tcf1 and Lef1 in pre-established CML, we further demonstrated an intrinsic requirement for these factors in LSC self-renewal. When combined with imatinib therapy, genetic targeting of Tcf1 and Lef1 potently diminished LSCs and conferred better protection to the CML recipients. LSCs are therefore more sensitive to loss of Tcf1 and Lef1 than HSCs in their self-renewal capacity. The differential requirements in HSCs and LSCs thus identify Tcf1 and Lef1 transcription factors as novel therapeutic targets in treating hematological malignancies, and inhibition of Tcf1/Lef1-regulated transcriptional programs may thus provide a therapeutic window to eliminate LSCs with minimal side effect on normal HSC functions.

KEYWORDS:

Wnt pathway; beta-catenin (β-catenin); gene regulation; hematopoietic stem cells; leukemic stem cells; self-renewal; transcription factor

PMID:
27044748
PMCID:
PMC4900264
DOI:
10.1074/jbc.M116.717801
[Indexed for MEDLINE]
Free PMC Article

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