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

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 patient samples and 30 control CD34+ samples, using the reverse phase protein arrays with 296 strictly validated antibodies. The multi-step “MetaGalaxy” analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIGs were associated with cytogenetics and mutational state, and with both favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib (ADEB)) identified three PrSIGs that did better with ADEB vs. ADE. When PrSIGs were studied in the context of genetic subgroups, PrSIGs 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 PrSIGs. Expression of certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.

Proteomic Profiling Identifies Specific Leukemic Stem Cell-Associated Protein Expression Patterns in Pediatric AML Patients

“…Limited literature exists on proteomic profiling of pediatric AML. Prior studies have employed RPPA and 2D gel electrophoresis together with matrix-assisted laser desorption ionization time-of-flight MS for proteomic analysis of unfractionated BM samples [ 57 , 58 , 59 ], and, recently, Nguyen et al compared the global proteomic profile of unfractionated leukemic bone marrow samples from 16 pediatric AML patients with or without core binding factor AML [ 60 ]. To the best of our knowledge, the use of highly purified cell populations instead of unfractionated BM samples has not previously been documented in pediatric AML.…”

Proteomic and phosphoproteomic measurements enhance ability to predict ex vivo drug response in AML

“…Most efforts to study how proteomics signatures can predict drug response have been previously evaluated in cell lines [ 16 , 17 ] and AML patient samples [ 18 ]. More recent efforts have characterized proteomics in patient samples using reverse phase proteomic assays (RPPA) in a pediatric AML cohort [ 19 ] as well as focusing explicity on phosphoproteomics measurements in AML related to FLT3 activity [ 20 ], showing how measuring protein and phosphorylation activity can better stratify patients and predict drug response. To date, however the integration of proteomic, phosphoproteomic, transcriptomic, and genomic data with drug response has not been evaluated in AML patient samples.…”

Proteomics: a new era in pediatric acute myeloid leukemia research

“…In this issue of Haematologica , Hoff et al 1 report their findings on the proteome of 500 pediatric cases of acute myeloid leukemia (AML) and 30 control CD34 + samples. Over the past few years, it has become clear that proteomic evaluations are critical to fully understand tumor biology and develop promising therapies in oncology.…”

“…One study evaluated a few proteins by two-dimensional gel electrophoresis and matrix assisted laser desorption ionization - time of flight (MALDI-TOF) analysis in three pediatric AML patients; 3 another study compared 31 proteins between 16 pediatric AML patients and five controls 4 and we recently evaluated global proteomic profiles of 16 pediatric AML patients. 5 We applaud Hoff et al 1 for collecting, analyzing, and sharing their data from a very large cohort of patients treated uniformly under a large cooperative group clinical trial protocol. The pediatric AML research community will gain valuable insights from these results and data for decades to come.…”

“…The paper by Hoff et al 1 thus marks the dawn of a new era in pediatric AML multi-omics research, instigating researchers to evaluate the global pediatric AML proteome and integrate its key components with relevant elements of other -omics profiles, such as the transcriptomic leukemia stem cell scores (LSC17, 8 and pLSC6 9 ), prognostic transcriptomic subgroups 10 and the pediatric AML methylome. 11 In this new era it will be imperative to develop and apply scientifically innovative and statistically rigorous methods of data analysis in order to obtain clinically and biologically useful insights based on widely reproducible results.…”