Clinical relevance of proteomic profiling in de novo pediatric acute myeloid leukemia: a Children’s Oncology Group study

• Type of Material: Article
• Authors: Fieke W Hoff, Universitair Medisch Centrum Groningen; Anneke D van Dijk, Universitair Medisch Centrum Groningen; Yihua Qiu, University of Texas Health Science Center at Houston; Chenyue W Hu, Rice University; Rhonda E Ries, Fred Hutchinson Cancer Research Center; Andrew Ligeralde, University of California, Berkeley; Gaye N Jenkins, Baylor College of Medicine; Robert B Gerbing, University of Southern California; Alan S Gamis, Children's Mercy Hospitals and Clinics; Richard Aplenc, The Children's Hospital of Philadelphia; Anders E Kolb, Emory University; Todd A Alonzo, University of Southern California; Soheil Meshinchi, Fred Hutchinson Cancer Research Center; Amina A Qutub, The University of Texas at San Antonio; Eveline SJM de Bont, Universitair Medisch Centrum Groningen; Terzah M Horton, Baylor College of Medicine; Steven M Kornblau, University of Texas Health Science Center at Houston
• Language: English
• Date: 2022-10-01
• Publisher: Ferrata Storti Foundation
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Ferrata Storti Foundation
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3324/haematol.2021.279672
• Title of Journal or Parent Work: Haematologica
• Volume: 107
• Issue: 10
• Start Page: 2329
• End Page: 2343
• Grant/Funding Information: TMH, RBG, ASG, RA, EAK, and RAA were funded by the NIH COG grants U10 CA98543, U10 CA98413, U10 CA180886, U24 CA196173 and U10 CA180899. TMH was funded by the NCI R01-CA164024, a grant from Hope on Wheels, Hyundaii Foundation, the St. Baldrick’s Foundation, and a grant from Takeda Pharmaceuticals. FWH was funded by the Junior Scientific Masterclaas and the Van der Meer-Boerema Stichting
• Keywords: Leukemia, Myeloid, Acute; Bortezomib; Proteins; Humans; Protein Array Analysis; Proteomics; Prognosis; Child
• Research Categories: Health Sciences, Oncology

Abstract

Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients’ samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies. The multistep MetaGalaxy analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIG were associated with cytogenetics and mutational state, and with favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib) identified three PrSIG that did better with ADE plus bortezomib than with ADE alone. When PrSIG were studied in the context of cytogenetic risk groups, PrSIG were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIG. Certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.