Back to Search
Start Over
HMGN1plays a significant role in CRLF2driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort
- Source :
- Oncogene; February 2022, Vol. 41 Issue: 6 p797-808, 12p
- Publication Year :
- 2022
-
Abstract
- The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2rDS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1loss of function on the leukemic burden. We demonstrated HMGN1KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2and HMGN1co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2rDS-ALL and identify HMGN1as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.
Details
- Language :
- English
- ISSN :
- 09509232 and 14765594
- Volume :
- 41
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Oncogene
- Publication Type :
- Periodical
- Accession number :
- ejs58406817
- Full Text :
- https://doi.org/10.1038/s41388-021-02126-4