Clinical relevance of proteomic profiling in <i>de novo</i> pediatric acute myeloid leukemia: a Children’s Oncology Group study
Fieke W. Hoff,
Anneke D. van Dijk,
Yihua Qiu,
Chenyue W. Hu,
Rhonda E. Ries,
Andrew Ligeralde,
Gaye N. Jenkins,
Robert B. Gerbing,
Alan S. Gamis,
Richard Aplenc,
E. Anders Kolb,
Todd A. Alonzo,
Soheil Meshinchi,
Amina A. Qutub,
Eveline S.J.M. de Bont,
Terzah M. Horton,
Steven M. Kornblau
Affiliations
Fieke W. Hoff
Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
Anneke D. van Dijk
Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Yihua Qiu
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Chenyue W. Hu
Department of Bioengineering, Rice University, Houston, TX, USA
Rhonda E. Ries
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Andrew Ligeralde
Biophysics, University of California, Berkeley, CA, USA
Gaye N. Jenkins
Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA
Robert B. Gerbing
University of Southern California, Los Angeles, CA, USA
Alan S. Gamis
Department of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA
Richard Aplenc
Division of Pediatric Oncology/Stem Cell Transplant, Children's Hospital of Philadelphia, Philadelphia, PA, USA
E. Anders Kolb
Nemours Center for Cancer and Blood Disorders, Emory University, Atlanta GA, USA
Todd A. Alonzo
University of Southern California, Los Angeles, CA, USA
Soheil Meshinchi
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Amina A. Qutub
Department of Biomedical Engineering, The University of Texas at San Antonio, USA;
Eveline S.J.M. de Bont
Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Terzah M. Horton
Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA
Steven M. Kornblau
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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.
