MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma

Abstract

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

Replicative Instability Drives Cancer Progression

“…Given this, elevated expression of MYBL2 mRNA is a robust marker of cells that are arrested prior to mitosis. In this study and our previous work, we have demonstrated that MYBL2 expression is tightly associated with the transcriptional upregulation of DNA repair genes that sense replication stress (12). This fits well when considering the mechanisms through which these signaling pathways coordinate cell cycle arrest following replication stress.…”

“…SBS4 features increased C>A transversions and is the byproduct of tobacco-smoke induced lesions (20). Importantly, MYBL2 High LUAD carried heterozygous losses in XPC and POLK which impair cellular ability to repair smoking induced lesions through NER (12). This analysis supports the notion that heterozygous losses of repair effectors functionally decrease pathway efficiency.…”

“…Previous work from our group revealed that elevated expression of the transcription factor MYB proto-oncogene like 2 (MYBL2) identified lung adenocarcinomas with genomic instability and wildtype BRCA (12). Our initial studies revealed that this MYBL2 High phenotype was associated with a unique set of cancer genetics and identified patients at risk for poor outcomes.…”

Replicative Instability Drives Cancer Progression

“…Previous work from our group revealed that elevated expression of the transcription factor MYB proto-oncogene like 2 (MYBL2) identified lung adenocarcinomas with genomic instability and wildtype BRCA [ 13 ]. In this manuscript, we sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors.…”

MYBL2 Gene Polymorphism Is Associated With Acute Lymphoblastic Leukemia Susceptibility in Children

“…MYBL2 has also been demonstrated to act as an oncogene in numerous studies (14,15). MYBL2 promotes the malignant development of cancer via regulating various cellular processes including apoptosis, proliferation, differentiation, invasion, metastasis, and replication stress (12,(16)(17)(18)(19)(20). The aberrant expression or dysfunction of MYBL2 has been validated in a variety of cancers including adult leukemia, breast cancer, prostate cancer, ovarian cancer, liver cancer, and lung cancer (19)(20)(21)(22)(23)(24)(25).…”