title: Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors.
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.
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China, ysy@cau.edu.cn.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Fengyin
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Xing
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Physics, The George Washington University, Washington, D. C. 20052, and.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 hai-hui-xue@uiowa.edu.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins
keywords: Wnt pathway; beta-catenin (β-catenin); gene regulation; hematopoietic stem cells; leukemic stem cells; self-renewal; transcription factor