Nuclear accumulation of SHIP1 mutants derived from AML patients leads to increased proliferation of leukemic cells

Nalaskowski, Marcus M.; Ehm, Patrick; Rehbach, Christoph; Nelson, Nina; Täger, Maike; Modest, Kathrin; Jücker, Manfred

doi:10.1016/j.cellsig.2018.05.006

Cited by 8 publications

(7 citation statements)

References 40 publications

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“…This gene encodes the inositol 5-phophatase know as SHIP-1 which acts as a negative regulator of the PI3K/AKT pathway. SHIP-1 affects cell proliferation in AML, due to mutations in the nuclear localization signature or phosphorylation site [ 55 ]. It has also been shown to act as an adaptor protein linked to wild type FLT3 signaling [ 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemic cells with diverse mutation spectra, which eventually leads to disease relapse. This genetic heterogeneity drives the activation of complex signaling pathways that is reflected at the protein level. This diversity makes it difficult to treat AML with targeted therapy, requiring custom patient treatment protocols tailored to each individual’s leukemia. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify genomic signatures that could predict patient-specific drug responses. However, there are inherent weaknesses in using only genetic and transcriptomic measurements as surrogates of drug response, particularly the absence of direct information about phosphorylation-mediated signal transduction. As a member of the Clinical Proteomic Tumor Analysis Consortium, we have extended the molecular characterization of this cohort by collecting proteomic and phosphoproteomic measurements from a subset of these patient samples (38 in total) to evaluate the hypothesis that proteomic signatures can improve the ability to predict response to 26 drugs in AML ex vivo samples. In this work we describe our systematic, multi-omic approach to evaluate proteomic signatures of drug response and compare protein levels to other markers of drug response such as mutational patterns. We explore the nuances of this approach using two drugs that target key pathways activated in AML: quizartinib (FLT3) and trametinib (Ras/MEK), and show how patient-derived signatures can be interpreted biologically and validated in cell lines. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to assess drug sensitivity in AML.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…In addition to the connection with AD, INPP5D and SHIP1 have been implicated as players and potential therapeutic targets for a range of diseases such as leukemias, , human cytomegalovirus, and autoimmune disorders including Chron’s disease and inflammatory bowel disease. − Small molecule SHIP1 regulators are already being studied for their anti-inflammatory effects in colitis and for their impact on cell signaling and immune response in cancer . Research in this area has a significant potential to increase the understanding of disease mechanisms as well as to discover new targets for therapies underlying AD and across other inflammatory and immunological disease spaces.…”

Section: Resultsmentioning

confidence: 99%

“…Inflammatory processes involving microglial regulation and cytokine release likely underly the role of SHIP1 in AD. 200,201 In addition to the connection with AD, INPP5D and SHIP1 have been implicated as players and potential therapeutic targets for a range of diseases such as leukemias, 202,203 human cytomegalovirus, 204 and autoimmune disorders including Chron's disease and inflammatory bowel disease. 205−207 Small molecule SHIP1 regulators are already being studied for their anti-inflammatory effects in colitis 207 and for their impact on cell signaling and immune response in cancer.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer’s Disease

Bartolo

Mortimer

Manter

et al. 2022

ACS Chem. Neurosci.

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Activation of microglial cells accompanies the progression of many neurodegenerative disorders, including Alzheimer's disease (AD). Development of molecular imaging tools specific to microglia can help elucidate the mechanism through which microglia contribute to the pathogenesis and progression of neurodegenerative disorders. Through analysis of published genetic, transcriptomic, and proteomic data sets, we identified 19 genes with microglia-specific expression that we then ranked based on association with the AD characteristics, change in expression, and potential druggability of the target. We believe that the process we used to identify and rank microglia-specific genes is broadly applicable to the identification and evaluation of targets in other disease areas and for applications beyond molecular imaging.

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“…This gene encodes the inositol 5-phophatase know as SHIP1 which acts as a negative regulator of the PI3K/AKT pathway. SHIP-1 affects cell proliferation in AML, due to mutational alteration of the nuclear localization signature or phosphorylation [46]. It has also been shown to act as an adaptor protein linking to wild type FLT3 signaling[47, 48].…”

Section: Resultsmentioning

confidence: 99%

Utilizing proteomics and phosphoproteomics to predict ex vivo drug sensitivity across genetically diverse AML patients

Tognon

Nestor

et al. 2021

Preprint

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Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemia. This genetic heterogeneity is difficult to treat using conventional therapies that are generally based on the detection of a single driving mutation. Thus, the use of molecular signatures, consisting of multiple functionally related transcripts or proteins, in making treatment decisions may overcome this hurdle and provide a more effective way to inform drug treatment protocols. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify signatures that could predict patient-specific drug responses. The Clinical Proteomic Tumor Analysis Consortium is in the process of extending this cohort to collect proteomic and phosphoproteomic measurements from a subset of these patient samples to evaluate the hypothesis that proteomic signatures can robustly predict drug response in AML patients. We sought to examine this hypothesis on a sub-cohort of 38 patient samples from Beat AML with proteomic and drug response data and evaluate our ability to identify proteomic signatures that predict drug response with high accuracy. For this initial analysis we built predictive models of patient drug responses across 26 drugs of interest using the proteomics and phosphproteomics data. We found that proteomics-derived signatures provide an accurate and robust signature of drug response in the AML ex vivo samples, as well as related cell lines, with better performance than those signatures derived from mutations or mRNA expression. Furthermore, we found that in specific drug-resistant cell lines, the proteins in our prognostic signatures represented dysregulated signaling pathways compared to parental cell lines, confirming the role of the proteins in the signatures in drug resistance. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to predict drug sensitivity in AML.

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Nuclear accumulation of SHIP1 mutants derived from AML patients leads to increased proliferation of leukemic cells

Cited by 8 publications

References 40 publications

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

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

Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer’s Disease

Utilizing proteomics and phosphoproteomics to predict ex vivo drug sensitivity across genetically diverse AML patients

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