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

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 acu...

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Published in:Leukemia & lymphoma 2024, Vol.65 (1), p.78-90
Main Authors: Contreras Yametti, Gloria P, Robbins, Gabriel, Chowdhury, Ashfiyah, Narang, Sonali, Ostrow, Talia H, Kilberg, Harrison, Greenberg, Joshua, Kramer, Lindsay, Raetz, Elizabeth, Tsirigos, Aristotelis, Evensen, Nikki A, Carroll, William L
Format: Article
Language:English
Subjects:
Humans
Leukemia, Myeloid, Acute
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Recurrence
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Summary: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. mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of mutations at relapse in most studies.
ISSN:1042-8194
1029-2403
DOI:10.1080/10428194.2023.2273752