Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis

Plo, Isabelle; Bellanné‐Chantelot, Christine; Mosca, Matthieu; Mazzi, Stefania; Marty, Caroline; Vainchenker, William

doi:10.3389/fendo.2017.00234

Cited by 46 publications

(62 citation statements)

References 106 publications

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“…Evolution to critical multi-lineage aplasia occurs before adulthood. 47,48 In the majority of cases, AR mutations in the MPL gene make the cells incapable of binding thrombopoietin; as a result circulating thrombopoietin levels are very high. 47 Nonsense mutations with a complete loss of Mpl give rise to a severe form (type I) while missense mutations and the presence of residual Mpl may give a milder form of the disease (type II).…”

Section: Congenital Amegakaryocytic Thrombocytopeniamentioning

confidence: 99%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

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In the late 19 th century improvements to the light microscope led to anucleate platelets being visualized in great numbers in human blood. Early pioneers in the field of platelet research included the Canadian William Osler, a Paris hematologist, George Hayem, who performed the first accurate platelet count, and the Italian Giulio Bizzozero. 1 In 1906, James Homer Wright confirmed that platelets were produced by bone marrow megakaryocytes. 2 When, in 1951, Harrington et al. 3 observed purpura in a child of a mother with immune thrombocytopenic purpura, a maternal factor was said to be destroying the platelets. Anti-platelet antibodies were identified as the cause and platelet transfusions, immunosuppressive therapy and splenectomy became standard treatments. Acquired thrombocytopenia, often with defective platelet function, has many causes. For example, it may be an immune response linked to blood transfusions and drugs, a direct consequence of viral or bacterial infections, be the result of other hematologic disorders or be secondary to many major illnesses. However, some thrombocytopenias are inherited and Professors Jean Bernard and Jean-Pierre Soulier in Paris were pioneers in this domain, describing in 1948 what they called in French "dystrophie thrombocytaire hémorragipare congénitale", later renamed the Bernard-Soulier syndrome (BSS). 4 Strikingly, many platelets were enlarged and some were giant. A key to the molecular defect was the platelet deficit of sialic acid, a negatively charged monosaccharide terminating many of the oligosaccharides of platelet glycoproteins (GP) and

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Section: Congenital Amegakaryocytic Thrombocytopeniamentioning

confidence: 99%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

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“…Thrombopoietin (TPO) is the main extrinsic regulator of platelet production [ 61 ] and binds to its cognate receptor, called MPL, which is a type 1 homodimeric cytokine receptor. Binding of TPO to MPL induces signalling through JAK2 and then downstream effectors such as STAT5, which regulates Bcl-xL expression [ 62 , 63 ]. In humans, homozygous loss of function mutations of MPL or TPO leads to a profound thrombocytopenia followed by an aplastic anemia, underscoring the role of the TPO/MPL axis in platelet production.…”

Section: Megakaryopoiesis and Its Regulationmentioning

confidence: 99%

“…In this latter case, they are due to the acquisition of somatic mutations in a haematopoietic stem cell, giving rise to myeloproliferative neoplasms (MPN) or myeloproliferative/myelodysplastic disease. Interestingly, whether they are inherited or acquired they are related to abnormalities in the TPO/MPL/JAK2 axis [ 62 ]. Inherited thrombocytosis are very rare.…”

Section: Diseases Of Platelet Numbers In Humansmentioning

confidence: 99%

Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

Josefsson

Vainchenker

James

2020

IJMS

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Blood platelets have important roles in haemostasis, where they quickly stop bleeding in response to vascular damage. They have also recognised functions in thrombosis, immunity, antimicrobal defense, cancer growth and metastasis, tumour angiogenesis, lymphangiogenesis, inflammatory diseases, wound healing, liver regeneration and neurodegeneration. Their brief life span in circulation is strictly controlled by intrinsic apoptosis, where the prosurvival Bcl-2 family protein, Bcl-xL, has a major role. Blood platelets are produced by large polyploid precursor cells, megakaryocytes, residing mainly in the bone marrow. Together with Mcl-1, Bcl-xL regulates megakaryocyte survival. This review describes megakaryocyte maturation and survival, platelet production, platelet life span and diseases of abnormal platelet number with a focus on the role of Bcl-xL during these processes.

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“…Inherited disorders of the hematopoietic system. The majority of inherited thrombocytosis are related to spontaneous activation of the MPL/JAK2 pathways due to MPL or JAK2 mutations 59 , 60 . The other mechanism is related to an excess of plasma thrombopoietin (TPO) due either to an excessive synthesis or to a defect in its clearance as a consequence of MPL mutations affecting receptor trafficking.…”

Section: Disease Associated With Abnormal Jak Activationmentioning

confidence: 99%

“…The other mechanism is related to an excess of plasma thrombopoietin (TPO) due either to an excessive synthesis or to a defect in its clearance as a consequence of MPL mutations affecting receptor trafficking. This excess of TPO induces JAK2 activation 59 , 60 .…”

Section: Disease Associated With Abnormal Jak Activationmentioning

confidence: 99%

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders

et al. 2018

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JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft-versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib) in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and one JAK1/JAK3 inhibitor (tofacitinib) in methotrexate-resistant rheumatoid arthritis. The non-approved compounds exhibited many off-target effects leading to neurological and gastrointestinal toxicities, as seen in clinical trials for MPNs. Ruxolitinib is a well-tolerated drug with mostly anti-inflammatory properties. Despite a weak effect on the cause of the disease itself in MPNs, it improves the clinical state of patients and increases survival in myelofibrosis. This limited effect is related to the fact that ruxolitinib, like the other type I JAK2 inhibitors, inhibits equally mutated and wild-type JAK2 (JAK2WT) and also the JAK2 oncogenic activation. Thus, other approaches need to be developed and could be based on either (1) the development of new inhibitors specifically targeting JAK2V617F or (2) the combination of the actual JAK2 inhibitors with other therapies, in particular with molecules targeting pathways downstream of JAK2 activation or the stability of JAK2 molecule. In contrast, the strong anti-inflammatory effects of the JAK inhibitors appear as a very promising therapeutic approach for many inflammatory and auto-immune diseases.

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Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis

Cited by 46 publications

References 106 publications

Inherited thrombocytopenias: history, advances and perspectives

Inherited thrombocytopenias: history, advances and perspectives

Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders

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