Mutational profile of childhood myeloproliferative neoplasms

Karow, Axel; Nienhold, Ronny; Lundberg, Pontus; Peroni, Edoardo; Putti, Maria Caterina; Randi, Maria Luigia; Skoda, Radek C.

doi:10.1038/leu.2015.205

Cited by 27 publications

(31 citation statements)

References 19 publications

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“…Current algorithms for the diagnosis of ET include molecular genetic studies for a pathogenic variant in one of these genes . ET is a rare disorder in childhood and, in striking contrast to adults, only 25–30% of children diagnosed with ET will have an acquired JAK2, MPL , or CALR mutation . Thus, 70–75% of children are classified as having “triple negative” disease.…”

Section: Introductionmentioning

confidence: 99%

“…X chromosome inactivation studies in girls with triple negative disease argued against clonal disease . However, targeted deep sequencing performed in two cohorts of children with ET revealed that 32–40% of those lacking JAK2 , MPL , or CALR mutations had somatic changes in one or more other genes previously implicated in myeloproliferative neoplasms . In these triple negative cases, any given other gene (e.g., ASXL1 and IRF8 ) was mutated in just a few patients.…”

Section: Introductionmentioning

confidence: 99%

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Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

Nelson

Marcogliese

Bergstrom

et al. 2016

Pediatr Blood Cancer

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JAK2, MPL, and CALR mutations, which underlie essential thrombocythemia (ET) in most adults, are infrequent in children. Consequently, additional tests are needed to confirm pediatric ET diagnoses. We report a child with suspected ET and p JAK2, MPL, and CALR analyses. Serum thrombopoietin was markedly elevated, leading to analysis of the thrombopoietin gene, TPHO, which contains an upstream open reading frame (uORF) known to repress THPO translation. Sequencing revealed a de novo, germline stopgain mutation in the uORF, explaining the elevated thrombopoietin and thrombocytosis. This suggests that screening thrombopoietin levels and, if elevated, THPO 5’ UTR sequencing could be diagnostic.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

Nelson

Marcogliese

Bergstrom

et al. 2016

Pediatr Blood Cancer

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“…This group of patients appears heterogeneous including some with a polyclonal hematopoiesis as previously shown in pediatric ETs. 49 Further studies using WES and RNA sequencing will be required to better understand the pathogenesis of these ETs. For personal use only.…”

Section: 41mentioning

confidence: 99%

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Cabagnols

Favale

Pasquier

et al. 2016

Blood

158

136

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Key Points• Enrichment of atypical MPL mutations in essential thrombocythemia.• MPLS204P and MPLY591N mutants are weak gain-offunction mutants.Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. (Blood. 2016;127(3):333-342)

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“…In particular, 2 3NEG cases presented a pre-PMF-like BM picture, supporting the idea that PMF can rarely occur in pediatric patients. 19 In the remaining 9 3NEG children with both clinical and histological features of ET, very low mutant allele burdens 20,21 and/or unusual MPN-associated mutations 22 might be present. Of note, histology was consistent with ST in 1 case, suggesting that a subset of 3NEG ET is indeed misdiagnosed ST. 23 We have recently observed 2 cases of putative 3NEG ET (BM not available for histologic evaluation) who spontaneously achieved hematological remission after 15 years of sustained thrombocytosis.…”

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confidence: 99%

Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study

Putti

Pizzi²,

Bertozzi

et al. 2017

Blood

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Mutational profile of childhood myeloproliferative neoplasms

Cited by 27 publications

References 19 publications

Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study

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