The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders

Scott, Linda M.; Campbell, Peter J.; Baxter, E. Joanna; Todd, Tony; Stephens, Philip J.; Edkins, Sarah; Wooster, Richard; Stratton, Michael R.; Futreal, P. Andrew; Green, Anthony

doi:10.1182/blood-2005-05-2087

Cited by 147 publications

(88 citation statements)

References 10 publications

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“…The presence of this mutation has also been described in other hematological malignancies, however, to a much lesser extent; ~3-5% of patients with MDS and <5% of patients with acute myeloid leukemia (AML) (5). The coexistence of del(5q) as sole cytogenetic abnormality and the JAK2 V617F mutation is even rarer occurring in a small subset of del(5q) MDS cases, and the optimal therapeutic approach in these patients remains to be elucidated (6).…”

Section: Introductionmentioning

confidence: 99%

Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

Hatzimichael

Lagos

Vassou

et al. 2016

Molecular and Clinical Oncology

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Abstract. Loss of a section of the long arm of chromosome 5, as a sole cytogenetic abnormality, characterizes a rare type of myelodysplastic syndrome [del(5q) MDS] and the co-existence of the JAK2 V617F mutation occurs in a small subset of these cases. Patients with isolated del(5q) MDS have a relatively favorable prognosis, with transformation to acute myeloid leukemia occurring in <10%, and their disease responds well to lenalidomide. However the optimal therapeutic approach for patients with del(5q) MDS in coexistence with the JAK2 V617F mutation, which is common to myeloproliferative neoplasms, remains to be elucidated. The present study reports a 77-year-old, transfusion-dependent female patient diagnosed with del(5q) MDS and a concomitant JAK2 V617F mutation. The patient was started on 10 mg lenalidomide daily for 21 days in a 28 day-cycle and within the first month of treatment, the patient became transfusion-independent. The only toxicity observed was grade 3 neutropenia, which was managed with transient treatment discontinuation and dose reduction on restart (5 mg). The patient achieved a complete cytogenetic and molecular response (normal karyotype and undetected JAK2 V617F mutation) within 6 months of treatment. However, 12 months post treatment initiation and while on hematological, cytogenetic and molecular response, the patient was unwilling to continue on treatment and lenalidomide was discontinued. The patient remains in hematological response, which lasts for >5 years despite treatment discontinuation. The present case highlights the coexistence of the JAK2 V617F mutation in del(5q) MDS and suggests that lenalidomide treatment is beneficial and effective for these patients, leading to complete hematological, cytogenetic and molecular response. Hematological response may be sustained for long periods of time, even following the discontinuation of the treatment.

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Section: Introductionmentioning

confidence: 99%

Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

Hatzimichael

Lagos

Vassou

et al. 2016

Molecular and Clinical Oncology

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“…The JAK2-V617F mutation was detected at low frequencies in acute myeloid leukemia (5%), myelodysplastic syndrome (3%), chronic myelomonocytic leukemia (6%), atypical myeloproliferative disorder (20%), hypereosinophilic syndrome (1%) and systemic mastocytosis (6%). [25][26][27][28][29][30] A thorough examination of the JAK2 gene in JAK2-V617F-negative PV patients led to the identification of various JAK2 mutations in exon 12 (JAK2-ex12). 24 Interestingly, JAK2-ex12 has so far been found only in PV but the rarity of this mutation makes it difficult to predict whether other MPN entities could also harbor this type of JAK2 mutation at lower frequencies.…”

Section: Introductionmentioning

confidence: 99%

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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“…[115][116][117][118][119][120] It is believed that at least in some of these cases the JAK2V617F mutation occurred before the acquisition of the Ph chromosome but unfortunately material was not available in any case to determine if the two abnormalities are part of the same clone or whether these cases have acquired two distinct diseases. In addition, a single AML patient with an FLT3 internal tandem duplication (FLT3-ITD), which is a typical and important molecular aberration in this disease entity, was found in combination with the JAK2V617F mutation.…”

Section: Jak2 Mutationsmentioning

confidence: 99%

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

et al. 2008

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The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders

Cited by 147 publications

References 10 publications

Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

Genetic complexity of myeloproliferative neoplasms

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

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