DNA Damage Response−Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients: Samples from Adults and from Children Enrolled in a Children’s Oncology Group Study

Author:

Hubner Stefan E.1ORCID,de Camargo Magalhães Eduardo S.2ORCID,Hoff Fieke W.3,Brown Brandon D.4,Qiu Yihua1,Horton Terzah M.5ORCID,Kornblau Steven M.1ORCID

Affiliation:

1. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

2. Department of Ageing Biology/ERIBA, University Medical Center Groningen, 9713 AV Groningen, The Netherlands

3. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA

4. Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

5. Department of Pediatrics, Dan Duncan Cancer Center, Texas Children’s Hospital, Houston, TX 77584, USA

Abstract

The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR−related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR−targeted therapies in AML patients.

Funder

Leukemia and Lymphoma

National Cancer Institute-NCI

National Institutes of Health, National Cancer Institute COG

St Baldrick’s Foundation

National Institutes of Health

National Cancer Institute

Takeda Pharmaceuticals

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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