Journal article
Targeting Tetramer-Forming GABP beta Isoforms Impairs Self-Renewal of Hematopoietic and Leukemic Stem Cells
Cell stem cell, Vol.11(2), pp.207-219
08/03/2012
DOI: 10.1016/j.stem.2012.05.021
PMCID: PMC3413094
PMID: 22862946
Abstract
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are both capable of self-renewal, with HSCs sustaining multiple blood lineage differentiation and LSCs indefinitely propagating leukemia. The GABP complex, consisting of DNA binding GABP alpha subunit and transactivation GABP beta subunit, critically regulates HSC multipotency and self-renewal via controlling an essential gene regulatory module. Two GABP beta isoforms, GABP beta 1L and GABP beta 2, contribute to assembly of GABP alpha(2)beta(2) tetramer. We demonstrate that GABP beta 1L/beta 2 deficiency specifically impairs HSC quiescence and survival, with little impact on cell cycle or apoptosis in differentiated blood cells. The HSC-specific effect is mechanistically ascribed to perturbed integrity of the GABP-controlled gene regulatory module in HSCs. Targeting GABP beta 1L/beta 2 also impairs LSC self-renewal in p210(BCR-ABL)-induced chronic myelogenous leukemia (CML) and exhibits synergistic effects with tyrosine kinase inhibitor imatinib therapy in inhibiting CML propagation. These findings identify the tetramer-forming GABP beta isoforms as specific HSC regulators and potential therapeutic targets in treating LSC-based hematological malignancy.
Details
- Title: Subtitle
- Targeting Tetramer-Forming GABP beta Isoforms Impairs Self-Renewal of Hematopoietic and Leukemic Stem Cells
- Creators
- Shuyang Yu - Roy J. and Lucille A. Carver College of MedicineXuefang Jing - Roy J. and Lucille A. Carver College of MedicineJohn D. Colgan - Roy J. and Lucille A. Carver College of MedicineDong-Mei Zhao - Roy J. and Lucille A. Carver College of MedicineHai-Hui Xue - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell stem cell, Vol.11(2), pp.207-219
- DOI
- 10.1016/j.stem.2012.05.021
- PMID
- 22862946
- PMCID
- PMC3413094
- NLM abbreviation
- Cell Stem Cell
- ISSN
- 1934-5909
- eISSN
- 1875-9777
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- Oberley Seed Grant from Holden Comprehensive Cancer Center, the University of Iowa AI080966; HL095540 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R21AI080966 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R01HL095540 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 08/03/2012
- Academic Unit
- Microbiology and Immunology; Anatomy and Cell Biology; Immunology; Internal Medicine
- Record Identifier
- 9984284340802771
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