JAK2V617F mutation in myelodysplastic syndrome (MDS) with del(5q) arises in genetically discordant clones

Sokol, Lubomir; Cáceres, Gisela; Rocha, Kenneth; Stockero, Kimberly J.; Dewald, D.W.; List, Alan F.

doi:10.1016/j.leukres.2009.09.016

Cited by 24 publications

(12 citation statements)

References 13 publications

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“…In fact, among myeloproliferative disorders, the 5q deletion has rarely been found, mostly in patients with primary myelofibrosis, and it is particularly rare in polycythaemia vera patients. Thus, it is difficult to determine whether the JAK-2 mutation represents a late event in an underlying myelodysplastic bone marrow, or rather an early event in the course of the disease; some authors have hypothesized that the two alterations may occur in two different and independent clones 1. Our clinical case seems to support this hypothesis since the myeloproliferative syndrome was diagnosed 14 years prior to the appearance of the 5q deletion.…”

Section: Discussionsupporting

confidence: 57%

Diagnosis of del(5q) MDS, 14 years after JAK-2 positive PV appearance: complete remission of both diseases with lenalidomide monotherapy

Vaccarino

Dogliotti

Marletto

et al. 2016

Mediterr J Hematol Infect Dis

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This is the report of the clinical case of a patient who presents the association of a JAK-2 positive chronic myeloproliferative neoplasia to a subsequent 5q- myelodysplastic syndrome, developed after about 14 years from the first diagnosis. Patient’s symptoms had rapidly worsened, and she became transfusion-dependent. Therapy with low-dose Lenalidomide quickly reduced the splenomegaly and completely brought white cells counts, haemoglobin, and platelets back to normal. After more than one year from the start, blood cell count is still normal. As far as we know, this is the first case of an effective treatment with Lenalidomide reported in this clinical setting.

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Section: Discussionsupporting

confidence: 57%

Diagnosis of del(5q) MDS, 14 years after JAK-2 positive PV appearance: complete remission of both diseases with lenalidomide monotherapy

Vaccarino

Dogliotti

Marletto

et al. 2016

Mediterr J Hematol Infect Dis

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“…It remains unclear whether the lenalidomide effect has a suppressive role against del(5q) cells and another independent activity against the JAK2 V617F mutated clone (10), since it has not been delineated whether the two genetic abnormalities involve the same or two distinct hematopoietic clones. Sokol et al (12) investigated the clonal origin of the JAK2 V617F mutation in a patient with del(5q) MDS presenting with thrombocytosis and normal hemoglobin, and suggested that the latter is the case.…”

Section: Discussionmentioning

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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“…Gene mutation screening in del(5q) MDS has been performed in previous studies, but most of these studies focused on a limited number of genes, and mainly employed traditional sequencing methods. 9,[34][35][36][37][38][39][40] Other studies have investigated a larger number of genes [41][42][43] but did not specifically focus on MDS cases with del(5q). To our knowledge, the present work is the first attempt to screen a large number of genes using a targeted next-generation sequencing approach in both early and advanced del(5q) MDS.…”

Section: Discussionmentioning

confidence: 99%

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

et al. 2013

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Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphismarray technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q-syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes.

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JAK2V617F mutation in myelodysplastic syndrome (MDS) with del(5q) arises in genetically discordant clones

Cited by 24 publications

References 13 publications

Diagnosis of del(5q) MDS, 14 years after JAK-2 positive PV appearance: complete remission of both diseases with lenalidomide monotherapy

Diagnosis of del(5q) MDS, 14 years after JAK-2 positive PV appearance: complete remission of both diseases with lenalidomide monotherapy

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

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

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