Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms

Schaub, Franz X.; Looser, Renate; Li, Sai; Hao-Shen, Hui; Lehmann, Thomas; Thewis, André; Skoda, Radek C.

doi:10.1182/blood-2009-09-245381

Cited by 162 publications

(136 citation statements)

References 25 publications

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“…This has the potential to inform on the order of acquisition of such variants during pre-clinical stages of leukemia development and suggests that future, larger studies may be able to inform which variants are associated with better response to chemotherapy and which ones are most likely to confer chemoresistance. For example, our finding that TET2 mutations can be lost at relapse confirms that mutations in this gene can be late 34 as well as early 35 events in AML. Also, further studies will be required to assess the prognostic value of DNMT3A R882H persistence at morphological remission, and whether this variant should be used for assessment of minimal residual disease.…”

supporting

confidence: 61%

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

et al. 2014

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ABSTRACTfers from the need for laborious library preparation, long turnaround times and reduced sensitivity for detecting long insertions such as FLT3-ITDs. 18 In this study, we employed the HaloPlex ® (Agilent Technologies) target enrichment system, which is based on digestion of genomic DNA to produce fragments tiling target regions, followed by sequence-specific annealing to custom-made probes followed by PCR-amplification to produce tagged amplicons for sequencing. This system uses little input DNA and promises a more affordable, quick, and efficient target enrichment that may be more suitable for analysis in diagnostic laboratories. 21 We used HaloPlex to study 24 recurrently mutated genes in 42 AML samples, mostly in the absence of matched normal DNA. Here we report its performance in identifying coding and copy number mutations affecting target genes.

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supporting

confidence: 61%

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

et al. 2014

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“…28 TET2 mutations are the most common genetic abnormality found in chronic myelomonocytic leukemia, being present in around 40% cases. 29,30 Although TET2 mutations can represent early molecular events in myeloproliferative neoplasms, in a recent study of JAK2 mutation-positive myeloproliferative neoplasms based on colony assays, genotyping for TET2 and JAK2 mutations, it was demonstrated that TET2 can be a late event in the progression of myeloproliferative neoplasms and may represent an acquired abnormality in a separate (JAK2 mutation-negative) clone. 31 It is intriguing to speculate that the acquisition of KRAS, TET2 or other mutagenic events could have played a role in the phenotypic shift observed in our cases.…”

Section: Discussionmentioning

confidence: 99%

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

et al. 2013

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Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (41 Â 10 9 /l) during the course of disease (5 men and 5 women; median age/range: 68 years/52-82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1-180) and persisted for a median period of 23 months (range: 2-57). Five patients died after developing monocytosis (range: 20-188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morphological shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt 'secondary' chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival.

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“…Some patients carry more than one mutation, and clonal hierarchy in such instances appears to be unpredictable. 17 JAK2 (Janus kinase 2) maps to chromosome 9p24. JAK2V617F is located on exon 14 and occurs in ϳ96% of patients with PV, 55% with ET, and 65% with PMF.…”

Section: Overview Of Mutations Associated With Bcr-abl1-negative Mpnsmentioning

confidence: 99%

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

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JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies. 1 Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories 2 : acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable. 1 Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as "classic" MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek. 3 In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases.JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1). 4 -7 These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia

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Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms

Cited by 162 publications

References 25 publications

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

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