Hereditary thrombocytosis not as innocent as thought? Development into acute leukemia and myelofibrosis

Posthuma, Hidde L. A.; Skoda, Radek C.; Jacob, Frank A.; Maas, A. P. C. van der; Valk, Peter J.M.; Posthuma, Eduardus F M

doi:10.1182/blood-2010-06-290718

Cited by 23 publications

(23 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Note: While on low dose aspirin since 1986 according to Michiels et al [17], all affected HET patients in the Dutch family were free of microvascular ischemic circulation disturbances and major thrombosis at a stable platelet count between 400x10 9 /L and around 1000x10 9 /L during life long follow up without the need of myelosuppressive treatment [17,37]. Table 1.…”

Section: Chromosome Abnormalitiesmentioning

confidence: 99%

See 1 more Smart Citation

Autosomal Dominant Hereditary Essential Thrombocythemia due to a Gain of Function Mutation in the Thrombopoietin (TPO) and JAK2 Gene as the Cause of Congenital Aspirin-Responsive Sticky Platelet Syndrome: Personal Experiences and Review of the Literature

Michiels¹

2014

J Hematol Thrombo Dis

View full text Add to dashboard Cite

Section: Chromosome Abnormalitiesmentioning

confidence: 99%

“…In 2010 Posthuma et al updated the natural history of case II2 and II8 of the second generation of the Dutch HET family [37]. Case II 2 of the Dutch HET family died at the age of 71 due to myelofibrosis with severe pancytopenia.…”

Section: Natural History Of Tpo-induced Autosomal Dominant Het In Thementioning

confidence: 99%

Autosomal Dominant Hereditary Essential Thrombocythemia due to a Gain of Function Mutation in the Thrombopoietin (TPO) and JAK2 Gene as the Cause of Congenital Aspirin-Responsive Sticky Platelet Syndrome: Personal Experiences and Review of the Literature

Michiels¹

2014

J Hematol Thrombo Dis

View full text Add to dashboard Cite

“…25 Overstimulation of the THPO pathway through either c-Mpl or THPO gain-of-function mutations are thought to contribute to chronic myeloproliferative disorders in patients who are negative for the JAK2 V617F and the CALR mutations. [19][20][21][49][50][51][52][53][54][55][56] The P106L mutation causing familiar HT may have a similar oncogenic potential, although myeloproliferative disorders have not (yet) developed in the families described here or previously. 9 In conclusion, our study uncovers that correct glycosylation, subcellular transport, distribution, and cell surface localization are not required for active c-Mpl downstream signaling, but that cell surface localization is required for controlling THPO levels and platelet homeostasis.…”

Section: Org Frommentioning

confidence: 99%

“…[19][20][21][49][50][51][52][53][54][55][56] The P106L mutation causing familiar HT may have a similar oncogenic potential, although myeloproliferative disorders have not (yet) developed in the families described here or previously.…”

mentioning

confidence: 99%

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

Stockklausner

Klotter

Dickemann

et al. 2015

Blood

View full text Add to dashboard Cite

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...

show abstract

“…8 Identification of the rare HT is also clinically important as an increased risk of thrombotic/hemorrhagic events, splenomegaly, bone marrow fibrosis, and also transformation to acute myeloid leukemia has been noted in previously documented HT kindred. 9,10 Therefore, these recent reports of germline JAK2 mutations in HT compel the incorporation of JAK2 gene analysis, including at least those exons that encode the pseudo-kinase and kinase domains, into the molecular diagnostic algorithm for suspected HT. 11 It is likely that further HT kindreds harbouring other JAK2 mutations will be discovered, with increasing characterization likely to improve our understanding of the genotype-phenotype relationship in both HT and MPN; the immediate goal being able to select appropriately targeted, JAK2 pathway inhibitor therapies currently available or in development for MPN patients.…”

mentioning

confidence: 99%

JAK2 mutations to the fore in hereditary thrombocythemia

Langabeer

2014

JAK-STAT

View full text Add to dashboard Cite

Hereditary thrombocytosis not as innocent as thought? Development into acute leukemia and myelofibrosis

Cited by 23 publications

References 5 publications

Autosomal Dominant Hereditary Essential Thrombocythemia due to a Gain of Function Mutation in the Thrombopoietin (TPO) and JAK2 Gene as the Cause of Congenital Aspirin-Responsive Sticky Platelet Syndrome: Personal Experiences and Review of the Literature

Autosomal Dominant Hereditary Essential Thrombocythemia due to a Gain of Function Mutation in the Thrombopoietin (TPO) and JAK2 Gene as the Cause of Congenital Aspirin-Responsive Sticky Platelet Syndrome: Personal Experiences and Review of the Literature

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

JAK2 mutations to the fore in hereditary thrombocythemia

Contact Info

Product

Resources

About