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GEP associated with drug resistance in adult AML

ABSTRACT: Acute myeloid leukemia (AML) patients are primarily resistant to induction chemotherapy in 20-50%. Previously it has been shown that resistance to the first cycle of induction chemotherapy is an independent prognostic factor. We investigated whether resistance to chemotherapy can be represented by gene-expression profiling, and which genes are associated with resistance. cDNA microarrays containing ~41.000 features were used to compare the gene-expression profile of AML blasts between 33 patients with good or poor response to induction chemotherapy. Data generated by cDNA-arrays were confirmed by quantitative RT-PCR. Using Significance Analysis of Microarrays, we identified a characteristic gene-expression profile which distinguished good- from poor-response AML samples. In hierarchical clustering analysis poor responders clustered together with normal CD34+ cells. Moreover, 13/40 (32.5%) genes highly expressed in poor responders are also overexpressed in hematopoietic stem/progenitor cells. Prediction analysis using 10-fold crossvalidation revealed 80% overall accuracy. Using the treatment response signature to predict the outcome in an independent test set of 104 AML patients, samples were separated into two subgroups with significantly inferior response rate (43.5% vs. 66.7%, P=.044), significantly shorter event-free and overall survival (P=.01 and P=.03, respectively) in the poor-response compared to the good-response signature group. In multivariate analysis, the treatment-response signature was an independent prognostic factor (hazard ratio, 2.1, 95 percent-confidence interval 1.2 to 3.6, P=.006). Resistance to chemotherapy in AML can be identified by gene-expression profiling before treatment and seems to be mediated by a transcriptional program active in hematopoietic stem/progenitor cells. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs

ORGANISM(S): Homo sapiens

PROVIDER: GSE4137 | GEO | 2006/02/01

SECONDARY ACCESSION(S): PRJNA95021

REPOSITORIES: GEO

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Project description:Background: A fundamental hallmark of cancer cells is their ability to sustain proliferative signaling and cell survival, reflected in a cellular chemotherapy response that is poorly understood. We questioned whether chemotherapy modulated phospho-signaling at 4 and 24 h in vivo could provide information about long-term survival in acute myeloid leukemia (AML), and if the signaling response to therapy was more informative than analysis at time of diagnosis. Methods: Peripheral blood was collected from 32 younger AML patients (age 16-74 years), before, 4- and 24 hours after start of induction chemotherapy. Samples were analyzed by 36-dimensional mass cytometry for assessment of alterations in immunophenotypes and intracellular signaling using unsupervised and supervised machine learning approaches. Results were validated by RNA sequencing and mass spectrometry proteomics (Super SILAC). Targeted sequencing was used to characterize patient samples for recurrent AML mutations. Drug sensitivity and resistance testing ex vivo was compared to activation of relevant signal transduction pathways and mutational profile. Findings: 5-year patient survival was accurately predicted in the leukemic cell population at 24 hours after therapy onset by phospho-proteins p-ERK1/2 (T202/Y204) and p-p38 (T180/Y182). RNA sequencing showed induction of MAPK target gene expression and the AP-1 transcription complex in patients with high p-ERK1/2. Super-SILAC proteomics confirmed an increase in the abundance of p38 prime target MAPKAPK2(MK2) 24 hours after start of induction therapy. Ex vivo drug sensitivity testing demonstrated high sensitivity to MEK inhibitors in the patient cells with high p-ERK1/2 measured at diagnosis or 24 hours after start of chemotherapy. Interpretation: Early single cell signaling response to chemotherapy provided precise prognostic information independent of stratification by genetics. We propose that early functional measurement of chemotherapy-potentiated MAPK pathway signaling could identify non-responders to intensive chemotherapy allowing precise treatment adjustment.

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GEP associated with drug resistance in adult AML

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