SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia

Abstract

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

Keywords:

• Relapsed acute lymphoblastic leukemia
• SETD2
• clonal evolution

Acknowledgements

The authors greatly appreciate the cell lines provided by Dr. Terzah Horton at Texas Children’s Cancer Center/Baylor College of Medicine and Dr. Benjamin Ebert at Brigham and Women’s Hospital, as well as the CRISPR plasmids from Dr. Feng Zhang and SETD2 plasmid from Dr. Sérgio De Almeida. The authors gratefully acknowledge the funding received to complete this work.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Additional information

Funding

WLC has received grants from the National Cancer Institute of Health [R01 CA140729-05], Hyundai Hope On Wheels (Hyundai Scholar Hope Grant), The Leukemia and Lymphoma Society Specialized Center for Research [7010-14], Perlmutter Cancer Center Arline and Norman M. Feinberg Pilot Grant for Lymphoid Malignancies, and the Perlmutter Cancer Center [P30 CA016087]. AT has received grants from the NCI/NIH (P01CA229086), NCI/NIH [R01CA252239], NCI/NIH [R01CA260028] and NIH/NCI [R01CA140729]. GCY and GR received funding from the Pediatric Cancer Foundation (Fellowship Training Grant). GCY received funding from Sohn Conference Foundation (Fellowship Training Grant) and Hyundai Hope on Wheels (Impact Award). We gratefully acknowledge the support of the NYU School of Medicine Cytometry and Cell Sorting Laboratory and the Genome Technology Center, which are supported by the NYU Langone Health Perlmutter Cancer Center Support Grant [P30 CA016087].