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A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia.
Klara Klein1, Sebastian Kollmann1, Angela Hiesinger1
1Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
Blood
|March 18, 2024
Summary
STAT5B gain-of-function mutations drive T- and natural killer (NK)-cell neoplasms. A new mouse model reveals STAT5BN642H causes indolent NK-LGLL that progresses to aggressive leukemia, offering insights into NK-cell malignancies.
Area of Science:
- Oncology
- Hematology
- Molecular Biology
Background:
- STAT5B gain-of-function mutations are common in T- and natural killer (NK)-cell neoplasms.
- The STAT5BN642H mutation drives T-cell leukemia but its role in NK-cell malignancies is not well understood.
Purpose of the Study:
- To investigate the role of the STAT5BN642H mutation in NK-cell malignancies.
- To develop a preclinical mouse model for studying NK-cell leukemia progression.
Main Methods:
- Generated tissue-specific STAT5BN642H mouse models (hematopoietic vs. NK-cell specific expression).
- Analyzed leukemia development and progression in mouse models.
- Compared transcriptional signatures of human NK-cell leukemia with murine models.
Main Results:
- Hematopoietic expression of STAT5BN642H led to aggressive T/NKT-cell leukemia.
- NK-cell specific expression resulted in indolent NK-large granular lymphocytic leukemia (NK-LGLL) that progressed to aggressive leukemia with age.
- Human NK-cell leukemia samples showed a transcriptional signature overlapping with murine leukemic NK cells.
Conclusions:
- The STAT5BN642H mutation can drive both indolent and aggressive NK-cell leukemia.
- The developed mouse model is the first to reliably replicate STAT5BN642H-driven NK-LGLL progression.
- This model serves as a valuable tool for studying NK-cell malignancy pathogenesis and therapeutic strategies.
