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High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

ABSTRACT: The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment. Stroma reprogrammed signaling networks and modified the sensitivity of acute myeloid leukemia samples to all three targeted inhibitors. Stroma activated AKT at Ser473 in the majority of samples treated with single-agent ABT737 or Nutlin-3a. This survival mechanism was partially abrogated by concomitant treatment with temsirolimus plus ABT737 or Nutlin-3a. Mapping the signaling networks revealed that combinations of two inhibitors increased the number of affected proteins in the targeted pathways and in multiple parallel signaling, translating into facilitated cell death. These results demonstrated that a mechanism-based selection of combined inhibitors can be used to guide clinical drug selection and tailor treatment regimens to eliminate microenvironment-mediated resistance in acute myeloid leukemia.

SUBMITTER: Zeng Z

PROVIDER: S-EPMC5685227 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

Zeng Zhihong Z Liu Wenbin W Tsao Twee T Qiu YiHua Y Zhao Yang Y Samudio Ismael I Sarbassov Dos D DD Kornblau Steven M SM Baggerly Keith A KA Kantarjian Hagop M HM Konopleva Marina M Andreeff Michael M

Haematologica 20170628 9

The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation i ...[more]

PMID: 28659338

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Project description:BackgroundCurrent outcome predictors based on "molecular profiling" rely on gene lists selected without consideration for their molecular mechanisms. This study was designed to demonstrate that we could learn about genes related to a specific mechanism and further use this knowledge to predict outcome in patients - a paradigm shift towards accurate "mechanism-anchored profiling". We propose a novel algorithm, PGnet, which predicts a tripartite mechanism-anchored network associated to epigenetic regulation consisting of phenotypes, genes and mechanisms. Genes termed as GEMs in this network meet all of the following criteria: (i) they are co-expressed with genes known to be involved in the biological mechanism of interest, (ii) they are also differentially expressed between distinct phenotypes relevant to the study, and (iii) as a biomodule, genes correlate with both the mechanism and the phenotype.ResultsThis proof-of-concept study, which focuses on epigenetic mechanisms, was conducted in a well-studied set of 132 acute lymphoblastic leukemia (ALL) microarrays annotated with nine distinct phenotypes and three measures of response to therapy. We used established parametric and non parametric statistics to derive the PGnet tripartite network that consisted of 10 phenotypes and 33 significant clusters of GEMs comprising 535 distinct genes. The significance of PGnet was estimated from empirical p-values, and a robust subnetwork derived from ALL outcome data was produced by repeated random sampling. The evaluation of derived robust network to predict outcome (relapse of ALL) was significant (p = 3%), using one hundred three-fold cross-validations and the shrunken centroids classifier.ConclusionTo our knowledge, this is the first method predicting co-expression networks of genes associated with epigenetic mechanisms and to demonstrate its inherent capability to predict therapeutic outcome. This PGnet approach can be applied to any regulatory mechanisms including transcriptional or microRNA regulation in order to derive predictive molecular profiles that are mechanistically anchored. The implementation of PGnet in R is freely available at http://Lussierlab.org/publication/PGnet.

Dataset Information

High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

Publications

High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

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