Journal
ONCOGENE
Volume 41, Issue 9, Pages 1324-1336Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-02168-8
Keywords
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Funding
- FPI Scholarship 2018 (Ministerio de Ciencia e Innovacion/MICINN)
- FPI Scholarship 2018 (Agencia Estatal de Investigacion/AEI)
- FPI Scholarship 2018 (Fondo Europeo de Desarrollo Regional/FEDER)
- undergraduate fellowship Beca de Introduccion a la Investigacion (Asociacion Espanola Contra el Cancer)
- Asociacion Pablo Ugarte
- Gilead Sciences International Scholar in Hematology/Oncology (Gilead)
- 2020 Leonardo Grant for Researchers and Cultural Creators (BBVA Foundation)
- Ministerio de Ciencia e Innovacion/MICINN [SAF2017-86327-R]
- Agencia Estatal de Investigacion/AEI [SAF2017-86327-R]
- Fondo Europeo de Desarrollo Regional/FEDER [SAF2017-86327-R]
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CXCL12 has novel regulatory functions in nuclear deformability and epigenetic changes of T-ALL cells, making it a potential pharmacological target for treating T-ALL dissemination.
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that comprises the accumulation of malignant T-cells. Despite current therapies, failure to conventional treatments and relapse are frequent in children with T-ALL. It is known that the chemokine CXCL12 modulates leukemia survival and dissemination; however, our understanding of molecular mechanisms used by T-ALL cells to infiltrate and respond to leukemia cells-microenvironment interactions is still vague. In the present study, we showed that CXCL12 promoted H3K9 methylation in cell lines and primary T-ALL cells within minutes. We thus identified that CXCL12-mediated H3K9 methylation affected the global chromatin configuration and the nuclear mechanics of T-ALL cells. Importantly, we characterized changes in the genomic profile of T-ALL cells associated with rapid CXCL12 stimulation. We showed that blocking CXCR4 and protein kinase C (PKC) impaired the H3K9 methylation induced by CXCL12 in T-ALL cells. Finally, blocking H3K9 methyltransferases reduced the efficiency of T-ALL cells to deform their nuclei, migrate across confined spaces, and home to spleen and bone marrow in vivo models. Together, our data show novel functions for CXL12 as a master regulator of nuclear deformability and epigenetic changes in T-ALL cells, and its potential as a promising pharmacological target against T-ALL dissemination.
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