Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia

Christopher B. Benton, Prajwal C. Boddu, Courtney D. DiNardo, Prithviraj Bose, Feng Wang, Rita Assi, Naveen Pemmaraju, K. C. Devendra, Sherry Pierce, Keyur Patel, Marina Konopleva, Farhad Ravandi, Guillermo Garcia-Manero, Tapan M. Kadia, Jorge Cortes, Hagop M. Kantarjian, Michael Andreeff, Srdan Verstovsek

Research output: Contribution to journalArticle

Abstract

Background: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. Methods: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). Results: Testing was performed for 2154 patients, and non-V617F/non–exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P <.001) and AML cohorts (5.2%; P <.001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P =.003). Conclusions: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.

Original languageEnglish (US)
Pages (from-to)1855-1866
Number of pages12
JournalCancer
Volume125
Issue number11
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

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Janus Kinase 2
Acute Myeloid Leukemia
Neoplasms
Primary Myelofibrosis
Mutation
Population
Genes

Keywords

  • acute myeloid leukemia
  • Janus kinase 2
  • myeloproliferative disorders
  • single-nucleotide polymorphism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Benton, C. B., Boddu, P. C., DiNardo, C. D., Bose, P., Wang, F., Assi, R., ... Verstovsek, S. (2019). Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia. Cancer, 125(11), 1855-1866. https://doi.org/10.1002/cncr.31986

Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia. / Benton, Christopher B.; Boddu, Prajwal C.; DiNardo, Courtney D.; Bose, Prithviraj; Wang, Feng; Assi, Rita; Pemmaraju, Naveen; Devendra, K. C.; Pierce, Sherry; Patel, Keyur; Konopleva, Marina; Ravandi, Farhad; Garcia-Manero, Guillermo; Kadia, Tapan M.; Cortes, Jorge; Kantarjian, Hagop M.; Andreeff, Michael; Verstovsek, Srdan.

In: Cancer, Vol. 125, No. 11, 01.06.2019, p. 1855-1866.

Research output: Contribution to journalArticle

Benton, CB, Boddu, PC, DiNardo, CD, Bose, P, Wang, F, Assi, R, Pemmaraju, N, Devendra, KC, Pierce, S, Patel, K, Konopleva, M, Ravandi, F, Garcia-Manero, G, Kadia, TM, Cortes, J, Kantarjian, HM, Andreeff, M & Verstovsek, S 2019, 'Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia', Cancer, vol. 125, no. 11, pp. 1855-1866. https://doi.org/10.1002/cncr.31986
Benton, Christopher B. ; Boddu, Prajwal C. ; DiNardo, Courtney D. ; Bose, Prithviraj ; Wang, Feng ; Assi, Rita ; Pemmaraju, Naveen ; Devendra, K. C. ; Pierce, Sherry ; Patel, Keyur ; Konopleva, Marina ; Ravandi, Farhad ; Garcia-Manero, Guillermo ; Kadia, Tapan M. ; Cortes, Jorge ; Kantarjian, Hagop M. ; Andreeff, Michael ; Verstovsek, Srdan. / Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia. In: Cancer. 2019 ; Vol. 125, No. 11. pp. 1855-1866.
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abstract = "Background: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. Methods: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). Results: Testing was performed for 2154 patients, and non-V617F/non–exon 12 JAK2 sequence variants were identified in 114 (5.3{\%}). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3{\%}) in comparison with the MPN (4.6{\%}; P <.001) and AML cohorts (5.2{\%}; P <.001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P =.003). Conclusions: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.",
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T1 - Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia

AU - Benton, Christopher B.

AU - Boddu, Prajwal C.

AU - DiNardo, Courtney D.

AU - Bose, Prithviraj

AU - Wang, Feng

AU - Assi, Rita

AU - Pemmaraju, Naveen

AU - Devendra, K. C.

AU - Pierce, Sherry

AU - Patel, Keyur

AU - Konopleva, Marina

AU - Ravandi, Farhad

AU - Garcia-Manero, Guillermo

AU - Kadia, Tapan M.

AU - Cortes, Jorge

AU - Kantarjian, Hagop M.

AU - Andreeff, Michael

AU - Verstovsek, Srdan

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. Methods: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). Results: Testing was performed for 2154 patients, and non-V617F/non–exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P <.001) and AML cohorts (5.2%; P <.001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P =.003). Conclusions: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.

AB - Background: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. Methods: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). Results: Testing was performed for 2154 patients, and non-V617F/non–exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P <.001) and AML cohorts (5.2%; P <.001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P =.003). Conclusions: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.

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