Nongenetic stochastic expansion of JAK2V617F-homozygous subclones in polycythemia vera?

Godfrey, Anna L.; Nangalia, Jyoti; Baxter, E. Joanna; Massie, Charles E.; Kent, David G.; Papaemmanuil, Elli; Campbell, Peter J.; Green, Anthony

doi:10.1182/blood-2014-09-603043

Cited by 4 publications

(2 citation statements)

References 10 publications

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“…The dominance of the JAK2 V617F -EGFR C329R/WT clone over the JAK2 V617F -EGFR WT/WT clone suggests that the aberrant RTK activity associated with the EGFR C329R mutant provides a clonal advantage. A previous study in two PV patients with multiple LOH clones (identified by the extent of uniparental disomy) did not identify somatic mutations unique to the dominant clone which might have explained its dominance 18 . They concluded that stochastic processes determine which LOH clone predominates.…”

Section: Resultsmentioning

confidence: 77%

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm

Casolari

Nguyen

Butcher

et al. 2017

Sci Rep

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We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

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Section: Resultsmentioning

confidence: 77%

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm

Casolari

Nguyen

Butcher

et al. 2017

Sci Rep

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“…8 Mutations of JAK2 exon 12, typically complex insertion/deletion events, are seen in roughly one third of cases of JAK2 V617F-negative PV. 9 Indirect dysregulation of JAK2 signalling occurs principally by activating mutations in MPL or CALR.…”

Section: -7mentioning

confidence: 99%

Genomics of Myeloproliferative Neoplasms

Zoi

Cross

2017

JCO

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Myeloproliferative neoplasms (MPN) are a group of related clonal hematological disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR-ABL1-negative MPN and a unifying therapeutic target. In addition, MPN show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continues to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems, and well as the need to standardize the laboratory methodologies that are employed.3

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After 10 years of JAK2V617F: Disease biology and current management strategies in polycythaemia vera

Grinfeld

Godfrey

2017

Blood Reviews

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Nongenetic stochastic expansion of JAK2V617F-homozygous subclones in polycythemia vera?

Cited by 4 publications

References 10 publications

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm

Genomics of Myeloproliferative Neoplasms

After 10 years of JAK2V617F: Disease biology and current management strategies in polycythaemia vera

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