STAT5B leukemic mutations, altering SH2 tyrosine 665, have opposing impacts on immune gene programs
STAT5B is a vital transcription factor for lymphocytes. Here, the function of two STAT5B mutations from human T-cell leukemias: one substituting tyrosine 665 with phenylalanine (STAT5B<sup>Y665F</sup>) and the other with histidine (STAT5B<sup>Y665H</sup>), was interrogated. In silico modeling predicted divergent energetic effects on homodimerization with a range of pathogenicity. In primary T cells in vitro, STAT5B<sup>Y665F</sup> showed gain-of-function, whereas STAT5B<sup>Y665H</sup> demonstrated loss-of-function. Introducing the mutation into the mouse genome illustrated that the gain-of-function <i>Stat5b</i> <sup>Y665F</sup> mutation resulted in accumulation of CD8<sup>+</sup> effector and memory and CD4<sup>+</sup> regulatory T cells, altering CD8<sup>+</sup>/CD4<sup>+</sup> ratios. In contrast, STAT5B<sup>Y665H</sup> "knock-in" mice showed diminished CD8<sup>+</sup> effector and memory and CD4<sup>+</sup> regulatory T cells. In contrast to WT STAT5B, the STAT5B<sup>Y665F</sup> variant displayed greater STAT5 phosphorylation, DNA binding, and transcriptional activity after cytokine activation, whereas the STAT5B<sup>Y665H</sup> variant resembled a null. The work exemplifies how joining in silico and in vivo studies of single nucleotides deepens our understanding of disease-associated variants, revealing structural determinants of altered function, defining mechanistic roles, and, specifically here, identifying a gain-of-function variant that does not directly induce hematopoietic malignancy.
Authors
- Molly Dalzell
- Sung‐Gwon Lee (ORCID: https://orcid.org/0000-0002-0928-9950)
- Xingmin Feng (ORCID: https://orcid.org/0000-0001-8018-2366)
- Alejandro V. Villarino (ORCID: https://orcid.org/0000-0001-8068-2176)
- Manja Meggendorfer (ORCID: https://orcid.org/0000-0002-9038-3265)
- Jichun Chen (ORCID: https://orcid.org/0000-0002-1038-471X)
- Lothar Hennighausen (ORCID: https://orcid.org/0000-0001-8319-9841)
- Priscilla A. Furth (ORCID: https://orcid.org/0000-0003-3883-0715)
- Claudia Haferlach
- John J. O’Shea (ORCID: https://orcid.org/0000-0002-6456-9752)
- Amy E. Keating (ORCID: https://orcid.org/0000-0003-4074-8980)
- Foster Birnbaum (ORCID: https://orcid.org/0000-0002-6062-2296)
- Rachael L. Philips (ORCID: https://orcid.org/0000-0001-5440-4594)
- Zhijie Wu (ORCID: https://orcid.org/0000-0003-3984-0819)
- Chengyu Liu (ORCID: https://orcid.org/0000-0003-1965-3020)
- Hye‐Kyung Lee (ORCID: https://orcid.org/0000-0002-7785-5942)
- Joseph Sexton (ORCID: https://orcid.org/0000-0002-7072-6283)
- Neal S. Young
- Aaron B. Schultz
Institutions
- National Institutes of Health (US)
- University of Miami (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Munich Leukemia Laboratory (Germany) (DE)
- National Heart, Lung, and Blood Institute (US)
- Sylvester Comprehensive Cancer Center (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2025-04-14
- DOI
- https://doi.org/10.26508/lsa.202503222
- Citations
- 4
- Primary Topic
- T-cell and Retrovirus Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- V Foundation for Cancer Research
- Leukemia Research Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases