Fast H3K9 methylation promoted by CXCL12 contributes to nuclear changes and invasiveness of T-acute lymphoblastic leukemia cells

• Published in: Oncogene Vol. 41; no. 9; pp. 1324 - 1336
• Main Authors: Madrazo, Elena, González-Novo, Raquel, Ortiz-Placín, Cándido, García de Lacoba, Mario, González-Murillo, África, Ramírez, Manuel, Redondo-Muñoz, Javier
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2022; Nature Publishing Group
• Subjects: 13/95; 14/10; 14/63; 38/61; 631/67/1990/283/2125; 631/67/2332; 631/80/79/2066; 631/80/84; 631/80/86/820; 64/60; 96/1; 96/95; Acute lymphoblastic leukemia; Animals; Apoptosis; Bone marrow; Cell Biology; Cell Line, Tumor; Cell Nucleus - metabolism; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chemokines; Chromatin; CXCL12 protein; CXCR4 protein; Deformability; Epigenetics; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - genetics; Histones - metabolism; Human Genetics; Humans; Internal Medicine; Invasiveness; Kinases; Leukemia; Lymphatic leukemia; Lymphocytes T; Malignancy; Medicine; Medicine & Public Health; Methylation; Mice; Microenvironments; Molecular modelling; Neoplasm Invasiveness; Oncology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein kinase C; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Spleen
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-02168-8

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.