Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases

He, Xin; Chen, Zhigang; Jiang, Yangyan; Qiu, Xi; Zhao, Xiaoying

doi:10.1186/1756-8722-6-11

Cited by 27 publications

(25 citation statements)

References 73 publications

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“…The enrichment in previously described rare signaling mutations 9 was striking in triple-negative ETs. One was a homozygous nonsense mutation in SH2B3.…”

Section: Discussionmentioning

confidence: 72%

“…7,8 In addition, other MPL mutants have already been described, more particularly in the extracellular domain of MPL in very rare ETs and PMFs, but without providing evidence for a gain-of-function. [8][9][10][11][12] SH2B3 loss-of-function mutations are present in ,1% of ET and PMF, but may not be sufficient to induce a MPN. 13,14 Recurrent mutations in the exon 9 of calreticulin (CALR) have been recently found in around 25% of ETs and PMFs.…”

Section: Introductionmentioning

confidence: 99%

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

Cabagnols

Favale

Pasquier

et al. 2016

Blood

158

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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“…The enrichment in previously described rare signaling mutations 9 was striking in triple-negative ETs. One was a homozygous nonsense mutation in SH2B3.…”

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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

Cabagnols

Favale

Pasquier

et al. 2016

Blood

158

136

View full text Add to dashboard Cite

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“…CAMT is a rare inherited syndrome characterized by thrombocytopenia at birth that rapidly progresses to bone marrow failure and pancytopenia. Since the first description of a disease-associated MPL mutation in CAMT in 1999, 1 more than 50 different genetic events have been reported for MPL, 2,3 and they are sometimes associated with defects in surface presentation. [4][5][6] Notably, the MPL Baltimore substitution (K39N) is associated with high platelet counts in patients of African American descent, despite incomplete processing and reduced Mpl protein levels.…”

Section: Introductionmentioning

confidence: 99%

Gene editing rescue of a novel MPL mutant associated with congenital amegakaryocytic thrombocytopenia

et al. 2017

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Key Points• We report unique familial cases of CAMT presenting with a novel MPL W272R mutation in the background of the activating MPL K39N mutation.• Function of mutant Mpl receptor can be rescued using 2 approaches: autophagic cell surface delivery and CRISPR-Cas9 gene editing.Thrombopoietin (Tpo) and its receptor (Mpl) are the principal regulators of early and late thrombopoiesis and hematopoietic stem cell maintenance. Mutations in MPL can drastically impair its function and be a contributing factor in multiple hematologic malignancies, including congenital amegakaryocytic thrombocytopenia (CAMT). CAMT is characterized by severe thrombocytopenia at birth, which progresses to bone marrow failure and pancytopenia. Here we report unique familial cases of CAMT that presented with a previously unreported MPL mutation: T814C (W272R) in the background of the activating MPL G117T(K39N or Baltimore) mutation. Confocal microscopy, proliferation and surface biotinylation assays, co-immunoprecipitation, and western blotting analysis were used to elucidate the function and trafficking of Mpl mutants. Results showed that Mpl protein bearing the W272R mutation, alone or together with the K39N mutation, lacks detectable surface expression while being strongly colocalized with the endoplasmic reticulum (ER) marker calreticulin.Both WT and K39N-mutated Mpl were found to be signaling competent, but single or double mutants bearing W272R were unresponsive to Tpo. Function of the deficient Mpl receptor could be rescued by using 2 separate approaches: (1) GRASP55 overexpression, which partially restored Tpo-induced signaling of mutant Mpl by activating an autophagy-dependent secretory pathway and thus forcing ER-trapped immature receptors to traffic to the cell surface; and (2) CRISPR-Cas9 gene editing used to repair MPL T814C mutation in transfected cell lines and primary umbilical cord blood-derived CD34 1 cells. We demonstrate proof of principle for rescue of mutant Mpl function by using gene editing of primary hematopoietic stem cells, which indicates direct therapeutic applications for CAMT patients.

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“…5,9,12,[16][17][18] Furthermore, the c-Mpl S505N mutation in the transmembrane region and the juxtamembrane c-Mpl W515L and W515K gain-of-function mutations have also been identified in patients with acquired diseases, such as essential thrombocytosis, myelofibrosis, and myeloproliferative diseases. [19][20][21][22] Thus, these mutations identify regions of the receptor that are important for its regulated function, which suggests that overstimulation of the THPO pathway may predispose to clonal hematopoietic disease. [22][23][24] Interestingly, c-Mpl mutations that result in loss of receptor function and have been located in the immediate vicinity of the activating c-Mpl P106L mutation in thrombocytopenia (R102P, F104S), which indicates that amino acids 102 to 106 within the first cytokine receptor homology module are critical for activity.…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis

Stockklausner

Klotter

Dickemann

et al. 2015

Blood

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Key Points• The c-Mpl activity in downstream signaling and in platelet homeostasis can be functionally separated.• The c-Mpl platelet homeostasis depends on correct processing and surface expression of the receptor, whereas downstream signaling does not.The interaction between thrombopoietin (THPO) and its receptor c-Mpl regulates downstream cytokine signaling and platelet homeostasis. Hereditary mutations of c-Mpl can either result in loss-of-function and thrombocytopenia or in gain-of-function and thrombocythemia (HT), and are important models to analyze the mechanism of c-Mpl activity. We have analyzed the effect of the c-Mpl P106L gain-of-function and the nearby loss-of-function R102P and F104S mutations, which cause HT or thrombocytopenia, respectively, on posttranslational processing, intracellular trafficking, cell surface expression, and cell proliferation. In contrast to R102P and F104S, the P106L mutant confers cytokine-independent growth and stimulates downstream signaling after THPO treatment in Ba/F3 cells. Despite their opposite function, R102P and P106L, both lead to abnormal subcellular receptor distribution, lack of membrane localization, impaired glycosylation, and elevated THPO serum levels in effected patients. These findings indicate that the activation of downstream signaling by c-Mpl P106L does not require correct processing, trafficking, and cell surface expression of c-Mpl, whereas the negative feedback loop controlling THPO serum levels requires cell surface expression of the receptor. Thus, we propose that the P106L mutation functionally separates the activity of c-Mpl in downstream signaling from that in maintaining platelet homeostasis. (Blood. 2015;125(7):1159-1169) IntroductionPlatelet production is stimulated by the interaction of the cytokine thrombopoietin (THPO) with its receptor c-Mpl on megakaryocytes and their progenitors with subsequent activation of several downstream pathways, including the Janus kinase/signal transducer and activator of transcription pathway, the phosphatidylinositol 3-kinase pathway, and the mitogen-activated protein kinase pathway. The homeostasis of platelet numbers in the blood is maintained by a negative feedback loop, which requires the clearance of THPO from the plasma by c-Mpl-carrying megakaryocytes and platelets.1 In addition, disruption of the signaling pathway by inactivating THPO or c-Mpl mutations can cause serious thrombocytopenia.2-4 By contrast, activating THPO or c-Mpl mutations can cause hereditary thrombocythemia (HT). [5][6][7][8][9][10][11][12] Interestingly, decreased expression of c-Mpl can also result in HT by high THPO levels, although the mechanism for this observation remains unknown. [13][14][15] Genotype analyses in HT have previously identified the transmembrane S505N, the extracellular N35K, and the P106L c-Mpl mutations to occur in Japanese, African American and Arabic populations, respectively. 5,9,12,[16][17][18] Furthermore, the c-Mpl S505N mutation in the transmembrane region and the juxtamembrane c-Mpl W515L and W515...

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Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases

Cited by 27 publications

References 73 publications

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

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

Gene editing rescue of a novel MPL mutant associated with congenital amegakaryocytic thrombocytopenia

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis

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