Opposing effects of NPM1wt and NPM1c mutants on AKT signaling in AML

Ren, Zhenhu; Shrestha, Mariusz; Sakamoto, Takashi; Melkman, Tali; Li, Meng; Cairns, Rob A.; Zacksenhaus, Eldad; Mak, Tak W.; Stambolic, Vuk; Minden, Mark D.; Wang, Jiance Atom

doi:10.1038/s41375-019-0621-7

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…Biologically meaningful overactive kinases were also identified in the other three cell lines. This included CSKN2A in PML-RARA driven NB4 cells [36], several kinases involved in the PRK/CREB-signaling in MLLdriven THP1 cells [37,38] and kinases of the AKT1pathway in the mutated NPM1-driven OCI-AML1 cells [39] (Suppl. Fig.…”

Section: Resultsmentioning

confidence: 99%

Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA)

et al. 2021

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Background Despite the introduction of targeted therapies, most patients with myeloid malignancies will not be cured and progress. Genomics is useful to elucidate the mutational landscape but remains limited in the prediction of therapeutic outcome and identification of targets for resistance. Dysregulation of phosphorylation-based signaling pathways is a hallmark of cancer, and therefore, kinase-inhibitors are playing an increasingly important role as targeted treatments. Untargeted phosphoproteomics analysis pipelines have been published but show limitations in inferring kinase-activities and identifying potential biomarkers of response and resistance. Methods We developed a phosphoproteomics workflow based on titanium dioxide phosphopeptide enrichment with subsequent analysis by liquid chromatography tandem mass spectrometry (LC-MS). We applied a novel Kinase-Activity Enrichment Analysis (KAEA) pipeline on differential phosphoproteomics profiles, which is based on the recently published SetRank enrichment algorithm with reduced false positive rates. Kinase activities were inferred by this algorithm using an extensive reference database comprising five experimentally validated kinase-substrate meta-databases complemented with the NetworKIN in-silico prediction tool. For the proof of concept, we used human myeloid cell lines (K562, NB4, THP1, OCI-AML3, MOLM13 and MV4–11) with known oncogenic drivers and exposed them to clinically established kinase-inhibitors. Results Biologically meaningful over- and under-active kinases were identified by KAEA in the unperturbed human myeloid cell lines (K562, NB4, THP1, OCI-AML3 and MOLM13). To increase the inhibition signal of the driving oncogenic kinases, we exposed the K562 (BCR-ABL1) and MOLM13/MV4–11 (FLT3-ITD) cell lines to either Nilotinib or Midostaurin kinase inhibitors, respectively. We observed correct detection of expected direct (ABL, KIT, SRC) and indirect (MAPK) targets of Nilotinib in K562 as well as indirect (PRKC, MAPK, AKT, RPS6K) targets of Midostaurin in MOLM13/MV4–11, respectively. Moreover, our pipeline was able to characterize unexplored kinase-activities within the corresponding signaling networks. Conclusions We developed and validated a novel KAEA pipeline for the analysis of differential phosphoproteomics MS profiling data. We provide translational researchers with an improved instrument to characterize the biological behavior of kinases in response or resistance to targeted treatment. Further investigations are warranted to determine the utility of KAEA to characterize mechanisms of disease progression and treatment failure using primary patient samples. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA)

et al. 2021

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“…These data indicate that FTO accelerates cell proliferation through activating PDGFRB/ERK signaling axis in NPM1-mutated AML. It has been reported that another PDGFRB downstream signaling, PI3K-AKT cascade, participates in leukemic cell proliferation advantage ( 66 , 67 ). Moreover, a recent study has revealed that FTO overexpression could activate PI3K-AKT cascade in bone marrow mesenchymal stem cells ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis

Xiao

Ren

et al. 2022

Front. Oncol.

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Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.

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“… [ 239 ] ARID1A/B mutations or deficiency Gastric, ovarian and endometrioid carcinoma, medulloblastoma [ 245 – 247 ] SF3B1 mutation Myelodysplastic/myeloproliferative neoplasms, melanoma, breast cancer, pancreatic cancer, prostate cancer, AML, etc. [ 254 , 255 ] NPM1 mutation AML [ 257 ] NM23-H1 Breast cancer, melanoma, etc. [ 248 ] CBL mutation Myeloid neoplasmas [ 249 ] BTK mutation or deficiency Follicular lymphoma [ 253 ] GPS2 mutation Breast cancer, medulloblastoma [ 250 – 252 ] CDH1 mutation or deficiency Gastric cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, etc.…”

Section: Biomarkers and Molecular Basis Of Response To Akt Inhibitors In Cancermentioning

confidence: 99%

“…Since mutations in another splicesomal gene, SURP and G-patch domain containing 1 ( SUGP1) , induce aberrant splicing identical or similar to that observed in mutant SF3B1 cancers, it remains to know whether SUGP1 mutations also confer hypersensitivity to Akt inhibitors [ 256 ]. Moreover, the frameshift mutations in nucleophosmin 1 (NPM1), a genetic event in about one-third of patients with acute myeloid leukemia (AML), lead to increased Akt activation that renders hypersensitivity to Akt inhibitors [ 257 ]. Whereas the wild-type NPM1 inhibits Akt phosphorylation, the AML-associated NPM1 mutants can prevent the nuclear localization of Akt and promote Akt phosphorylation [ 257 ].…”

Section: Biomarkers and Molecular Basis Of Response To Akt Inhibitors In Cancermentioning

confidence: 99%

“…Moreover, the frameshift mutations in nucleophosmin 1 (NPM1), a genetic event in about one-third of patients with acute myeloid leukemia (AML), lead to increased Akt activation that renders hypersensitivity to Akt inhibitors [ 257 ]. Whereas the wild-type NPM1 inhibits Akt phosphorylation, the AML-associated NPM1 mutants can prevent the nuclear localization of Akt and promote Akt phosphorylation [ 257 ]. Of note, overexpression of NPM1 has been detected in solid tumors including colorectal and hepatocellular carcinoma [ 258 ].…”

Section: Biomarkers and Molecular Basis Of Response To Akt Inhibitors In Cancermentioning

confidence: 99%

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Targeting Akt in cancer for precision therapy

et al. 2021

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Biomarkers-guided precision therapeutics has revolutionized the clinical development and administration of molecular-targeted anticancer agents. Tailored precision cancer therapy exhibits better response rate compared to unselective treatment. Protein kinases have critical roles in cell signaling, metabolism, proliferation, survival and migration. Aberrant activation of protein kinases is critical for tumor growth and progression. Hence, protein kinases are key targets for molecular targeted cancer therapy. The serine/threonine kinase Akt is frequently activated in various types of cancer. Activation of Akt promotes tumor progression and drug resistance. Since the first Akt inhibitor was reported in 2000, many Akt inhibitors have been developed and evaluated in either early or late stage of clinical trials, which take advantage of liquid biopsy and genomic or molecular profiling to realize personalized cancer therapy. Two inhibitors, capivasertib and ipatasertib, are being tested in phase III clinical trials for cancer therapy. Here, we highlight recent progress of Akt signaling pathway, review the up-to-date data from clinical studies of Akt inhibitors and discuss the potential biomarkers that may help personalized treatment of cancer with Akt inhibitors. In addition, we also discuss how Akt may confer the vulnerability of cancer cells to some kinds of anticancer agents.

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Opposing effects of NPM1wt and NPM1c mutants on AKT signaling in AML

Cited by 12 publications

References 15 publications

Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA)

Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA)

Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis

Targeting Akt in cancer for precision therapy

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