Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders

Královics, Róbert; Skoda, Radek C.

doi:10.1016/j.blre.2004.02.002

Cited by 53 publications

(49 citation statements)

References 107 publications

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“…In some patients, uniparental disomy on chromosome 9p (9pUPD) results in transition of cells heterozygous for JAK2-V617F to homozygosity for the mutation (XX). 10,59 In all cases examined so far, JAK2-V617F and JAK2-ex12 mutations were acquired somatically in these families, never inherited through the germ line. 60,61 Thus, the unknown germline mutation inherited in these families predisposes carriers to somatically acquire JAK2 mutations and develop MPN.…”

Section: Clonality In Mpnmentioning

confidence: 93%

“…9 Growth factor hypersensitivity of progenitors in MPN was later further elaborated in different culture systems and extended to ET and PMF. 10 After abnormal cytokine responsiveness of hematopoietic progenitors in MPN had been established, a lot of attention was devoted to cytokine signaling. Initial studies targeted the cytokine receptors and their ligands, and later the individual signaling proteins and transcription factors were examined.…”

Section: Introductionmentioning

confidence: 99%

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Genetic complexity of myeloproliferative neoplasms

Královics

2008

Leukemia

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Oncogenic mutations in JAK2 and MPL genes have recently been identified in myeloproliferative neoplasms (MPNs). In addition to these mutations, cytogenetic aberrations are frequently present at diagnosis but their role in the pathogenesis remains unclear. Two models of MPN pathogenesis have recently emerged based on either a single-hit or a multi-hit concept. The first model proposes that the acquisition of JAK2 mutations is the disease-initiating event, causing both the onset of disease phenotype and establishment of clonal hematopoiesis. The second model postulates the existence of 'pre-JAK2' mutations that establish clonal hematopoiesis before acquisition of JAK2 mutations and onset of disease phenotype. In this review, the two models have been critically evaluated in the context of the latest findings. At present, neither of the two models can be universally applied to all MPN patients due to their genetic heterogeneity. It is likely that the disease pathogenesis in some patients follows the first, and in other patients, the second model. Thus, the somatic mutations in MPN do not seem to be acquired in a predetermined order as seen in other malignancies, but occur randomly. Furthermore, the role of uniparental disomy in MPN and certain aspects of MPN therapy are discussed.

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Section: Clonality In Mpnmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Genetic complexity of myeloproliferative neoplasms

Královics

2008

Leukemia

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“…5 Erythroid progenitors were also shown to be hypersensitive to other cytokines/growth factors, including interleukin (IL)-3, 6 insulin-like growth factor-1, 4 stem cell factor 7 and granulocytemacrophage colony stimulating factor. 8 Unlike in hereditary erythrocytosis where mutations in the Epo receptor (EpoR) cytoplasmic domain (or alternatively, in the von Hippel-Lindau (VHL) protein) may be evident (reviewed by Kralovics and Skoda 9 ), similar studies failed to identify EpoR mutations in patients with PV. 10,11 Similarly, in early studies, endogenous megakaryocyte colony growth did not appear to be associated with mutations in c-mpl (MPL), the thrombopoietin receptor, in ET or PMF patients.…”

Section: Pre-jak2v617f Eramentioning

confidence: 99%

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

2007

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“…11 However, these mutations account for only a minority of HT, since in most cases the disease-causing gene remains unknown; furthermore, true prevalence of HT is likely underestimated because it is generally asymptomatic and often not adequately sought. Another form of HT is due to a lysine to asparagine substitution at amino acid 39 (G1238T) in MPL (Mpl Baltimore), which has been described exclusively in African-American descendants.…”

Section: Causes Of Thrombocytosismentioning

confidence: 99%

Thrombocytosis and Thrombosis

Vannucchi¹,

Barbui²

2007

Hematology

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The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.

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Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders

Cited by 53 publications

References 107 publications

Genetic complexity of myeloproliferative neoplasms

Genetic complexity of myeloproliferative neoplasms

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

Thrombocytosis and Thrombosis

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