Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Saint‐Martin, Cécile; Stefano, Antonio Di; Lenglet, Gaëlle; Marty, Caroline; Keren, Boris; Pasquier, Florence; Valle, Véronique Della; Secardin, Lise; Leroy, Gwendoline; Mahfoudhi, Emna; Grosjean, Sarah; Droin, Nathalie; Diop, M’Boyba; Dessen, Philippe; Charrier, Sabine; Palazzo, Alberta; Merlevede, Jane; Meniane, Jean-Côme; Delaunay-Darivon, Christine; Fuseau, Pascal; Isnard, F; Casadevall, Nicole; Solary, Éric; Debili, Najet; Bernard, Olivier A.; Raslová, Hana; Najman, A; Vainchenker, William; Bellanné‐Chantelot, Christine; Plo, Isabelle

doi:10.1038/ng.3380

Cited by 112 publications

(83 citation statements)

References 63 publications

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“…85 It appears that these changes operate via independent pathways: RBBP6 mutations affect the p53 pathway and thereby influence the response to apoptotic stimuli and the risk of developing further mutations, while ATG2B and GSKIP overexpression promote megakaryopoiesis via increased thrombopoietin sensitivity.…”

Section: Germline Variationmentioning

confidence: 99%

“…125 In addition, germline copy number variations on chromosome 14, which are associated predominantly with an ET phenotype, appear to result in increased sensitivity to TPO and cytokine-independent growth, even in the absence of a phenotypic driver mutation. 85 Other non-genetic host factors may also influence MPN phenotype. For example, iron deficiency may constrain erythropoiesis and promote thrombocytosis, skewing towards an ET phenotype.…”

Section: Role Of Non-tumor Factorsmentioning

confidence: 99%

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Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

2016

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Section: Germline Variationmentioning

confidence: 99%

Section: Role Of Non-tumor Factorsmentioning

confidence: 99%

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

2016

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“…25 Whole-exome sequencing WES was performed on genomic DNA (1 mg) from paired samples (granulocytes vs T cells) The final libraries were indexed, pooled, and sequenced on an Illumina HiSeq-2000 sequencer. Only nonsynonymous and splice-site mutations were further pursued.…”

Section: Cgh Arraysmentioning

confidence: 99%

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Cabagnols

Favale

Pasquier

et al. 2016

Blood

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136

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Key Points• Enrichment of atypical MPL mutations in essential thrombocythemia.• MPLS204P and MPLY591N mutants are weak gain-offunction mutants.Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. (Blood. 2016;127(3):333-342)

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“…Increased Wnt signaling activity plays a role in various cancers, neurological diseases, fibrosis, and other diseases (55,56). A duplication of the chromosomal region encoding GSKIP predisposes to myeloid lymphoma, presumably due to increased GSKIP protein, inhibition of GSK3␤, and increased Wnt signaling (57). A general challenge in targeting the Wnt signaling pathway for therapeutic purposes is its complex crosstalk with MAPK, bone morphogenetic protein (BMP), Hedgehog, Notch, cAMP/PKA, and other pathways (50,56,58,59).…”

Section: Lihrleavqrtreamentioning

confidence: 99%

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

Dema

Schröter

Perets

et al. 2016

Journal of Biological Chemistry

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The A-kinase anchoring protein (AKAP) GSK3␤ interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3␤ (GSK3␤). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3␤ are required for the regulation of ␤-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ␤-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ␤-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ␤-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3␤ facilitates control of the destabilizing phosphorylation of ␤-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ␤-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ␤-catenin. The regulation of ␤-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3␤, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3␤ is a conserved GSK3␤ interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3␤ by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases.A-kinase anchoring proteins (AKAPs) 3 are a family of about 50 scaffolding proteins. Their conserved function is the compartmentalization of protein kinase A (PKA). PKA holoenzyme consists of a dimer of regulatory (RI␣, RI␤, RII␣, or RII␤) and two catalytic subunits each bound to one R subunit. AKAPs directly interact with R subunits and tether the kinase to defined cellular compartments such as vesicles, the sarcoplasmic reticulum, or the cytoskeleton. This compartmentalization confers a tight spatiotemporal control to PKA signaling, and enables PKA to elicit a specific cellular response to each of the many stimuli that cause cAMP elevation and thereby lead to activation of this ubiquitous kinase. AKAPs directly interact with further signaling proteins, thus mediating crosstalk between signaling systems: phosphatases, dephosphorylating PKA-phosphorylated substrates, adenylyl cyclases, synthesizing cAMP, and phosphodiesterases (PDEs), hydrolyzing cAMP. Several AKAPs bind further kinases such as protein kinase C (PKC), which are activated by signals other than cAMP, e.g. Ca 2ϩ . AKAPs and their interactions play key roles in a variety of physiological processes such as vasopressin-mediated water reabsorption in renal principal cells and cardiac myocyte contractility (1-5, 7, 8).A new example...

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Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Cited by 112 publications

References 63 publications

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

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