STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output

Geqiang Li; Zhengqi Wang; Yi Zhang; Zizhen Kang; Eleonora Haviernikova; Yongzhi Cui; Lothar Hennighausen; Richard Moriggl; Demin Wang; William Tse; Kevin D Bunting

doi:10.1016/j.exphem.2007.08.026

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STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output

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STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output

Geqiang Li, Zhengqi Wang, Yi Zhang, Zizhen Kang, Eleonora Haviernikova, Yongzhi Cui, Lothar Hennighausen, Richard Moriggl, Demin Wang, William Tse, …

Experimental hematology, Vol.35(11), pp.1684-1694

2007

DOI: 10.1016/j.exphem.2007.08.026

PMCID: PMC2134320

PMID: 17976521

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Abstract

Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of hematopoietic development and its impaired activation is associated with hematopoietic and immune cell defects. However, much of this information has been learned from knockout mice that still retain the potential for expression of STAT5 proteins that are N-terminally truncated due to alternative internal translation initiation codons. The goal of these studies was to use transplantation-based assays to analyze the degree of STAT5ΔN activity in hematopoietic stem cells (HSC) and throughout lymphomyeloid development. We have directly compared E14.5 fetal liver cells from mice with potential to express STAT5abΔN (STAT5ab ΔN/ΔN) with mice completely lacking STAT5a and STAT5b (STAT5ab null/null). We have also utilized retroviral complementation of STAT5ab null/null fetal liver HSC to enforce expression of full-length STAT5a or STAT5a lacking the first 136 amino acids (STAT5aΔN). We report that STAT5 is required for HSC, lymphocyte, and erythrocyte development. We demonstrate that restored expression of STAT5a in STAT5ab null/null HSC provides a strong selective advantage, correcting T- and B-lymphocyte and erythrocyte development. Interestingly, Gr-1 + blood cells were inversely correlated with B lymphocytes and both were normalized by STAT5a expression. In contrast, transduction of STAT5aΔN only provided partial B-lymphocyte development. These studies define the role of STAT5 in maintaining normal lymphoid vs myeloid balance during hematopoiesis and highlight a major role for the N-domain in HSC function. The platform of retroviral complementation described here will be particularly useful for future studies to subdefine the N-domain regions that are critical for hematopoiesis.

Details

Title: Subtitle: STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output
Creators: Geqiang Li - Case Western Reserve University
Zhengqi Wang - Case Western Reserve University
Yi Zhang - Case Western Reserve University
Zizhen Kang - Case Western Reserve University
Eleonora Haviernikova - Case Western Reserve University
Yongzhi Cui - National Institutes of Health
Lothar Hennighausen - National Institutes of Health
Richard Moriggl - Ludwig Boltzmann Institute for Cancer Research
Demin Wang - Medical College of Wisconsin
William Tse - Case Western Reserve University
Kevin D Bunting - Case Western Reserve University
Resource Type: Journal article
Publication Details: Experimental hematology, Vol.35(11), pp.1684-1694
DOI: 10.1016/j.exphem.2007.08.026
PMID: 17976521
PMCID: PMC2134320
NLM abbreviation: Exp Hematol
ISSN: 0301-472X
eISSN: 1873-2399
Publisher: Elsevier Inc
Language: English
Date published: 2007
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984201117402771

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