Abstract The Janus kinase -signal transducer and activator of transcription (JAK-STAT) pathway plays pivotal roles in the regulation of cell proliferation, differentiation, migration and apoptosis, which is closely related with the development of hematopoietic cells and some hematological diseases. As an important signaling axis in JAK-STAT pathway, abnormally activated JAK2-STAT signaling is involved in the development of the hematological malignancies. JAK2V617F mutation is the important molecular pathogenesis of myeloproliferative disorders. Recent studies have demonstrated that JAK2 mutations are present in different acute leukemia subtypes and the frequency of mutations is different and that JAK2 mutations might be closely correlated with acute leukemia formation, treatment and prognosis. The pathogenic mechanism of JAK2 mutations has not been completely elucidated. JAK2 mutations might lead to JAK-STAT overactivation, resulting in the excessive proliferation, apoptosis resistance and differentiation blocking of blood cells. JAK2 inhibitors have been rapidly developed as targeted therapies for hematological disorders with JAK2 mutations. This article mainly focuses on recent studies about the role of JAK2 mutations in the pathogenesis, clinical characteristics and targeted therapies of acute leukemia.
Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005:a report from the children's oncology group[J]. J Clin Oncol, 2012, 30(14):1663-1669.
[2]
Zhai XW, Cheng FW, Lee V, et al. Improved survival outcome of childhood acute myeloid leukemia with intensified chemotherapy in Chinese children[J]. Pediatr Hematol Oncol, 2011, 28(4):269- 278.
Offenmuller S, Ravindranath Y, Goyette G, et al. Focused screening of a panel of cancer-related genetic polymorphisms reveals new susceptibility loci for pediatric acute lymphoblastic leukemia[J]. Pediatr Blood Cancer, 2014, 61(8):1411-1415.
[8]
Gutierrez-Camino A, Lopez-Lopez E, Martin-Guerrero I, et al. Intron 3 of the ARID5B gene:a hot spot for acute lymphoblastic leukemia susceptibility[J]. J Cancer Res Clin Oncol, 2013, 139(11):1879-1886.
[9]
Seavey MM, Dobrzanski P. The many faces of Janus kinase[J]. Biochem Pharmacol, 2012, 83(9):1136-1145.
[10]
Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies:Implications for future therapeutic approaches[J]. Drug Resistance Updates, 2010, 13(3):67-78.
[11]
Ungureanu D, Wu J, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling[J]. Nature Struct Mol Biol, 2011, 18(9):971-976.
[12]
Lee HJ, Daver N, Kantarjian HM, et al. The role of JAK pathway dysregulation in the pathogenesis and treatment of acute myeloid leukemia[J]. Clin Cancer Res, 2013,9(2):27-335.
[13]
Silvennoinen O, Ungureanu D, Niranjan Y, et al. New insights into the structure and function of the pseudokinase domain in JAK2[J]. Bioch Society Transact, 2013, 41(4):1002-1007.
[14]
Brooks AJ, Dai W, O'Mara ML, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor[J]. Science, 2014, 344(6185):1249783.
[15]
Agrawal S, Gollapudi S, Su H, et al. Leptin activates human B cells to secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway[J]. J Clin Immunol, 2011, 31(3):472-478.
[16]
Zhang F, Li C, Halfter H, et al. Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells[J]. Oncogene, 2003, 22(6):894-905.
[17]
Dawson MA, Bannister AJ, Göttgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin[J]. Nature, 2009, 461(7265):819-822.
[18]
Zamora L, Xandri M, Garcia O, et al. Association of JAK2 mutation status and cytogenetic abnormalities at diagnosis in myeloproliferative neoplasms and myelodysplastic/ myeloproliferative neoplasms[J]. Am J Clin Pathol, 2012, 137(4):677-678.
[19]
Salmoiraghi S, Montalvo ML, D'Agostini E, et al. Mutations and chromosomal rearrangements of JAK2:not only a myeloid issue[J]. Expert Rev Hematol, 2013, 6(4):429-439.
Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm[J]. Current Opin Hematol, 2014, 21(2):65-71.
[22]
Cancer Genome Atlas Research Network. Genomic and epigenomic Landscapes of adult de novo acute myeloid leukemia[J]. NEJM, 2013, 368(22):2059-2074.
[23]
Zhang SJ, Rampal R, Manshouri T, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome[J]. Blood, 2012, 119(19):4480-4485.
[24]
Wang M, He N, Tian T, et al. Mutation analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese patients with myeloproliferative neoplasms[J]. Biomed Res Int, 2014, 2014:485645.
[25]
Nielsen C, Bojesen SE, Nordestgaard BG, et al. JAK2V617F somatic mutation in the general population:myeloproliferative neoplasm development and progression rate[J]. Haematologica, 2014, 99(9):1448-1455.
[26]
Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias[J]. Cancer Res, 2010, 70(2):447-452.
[27]
Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias[J]. Oncogene, 2006, 25(9):1434-1436.
[28]
Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms[J]. Proc Natl Acad Sci U S A, 2014, 111(50):E5401-E5410.
[29]
Beer PA, Delhommeau F, LeCouedic JP, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm[J]. Blood, 2010, 115(14):2891- 2900.
[30]
Swaminathan S, Madkaikar M, Ghosh K, et al. Novel immunophenotypic and morphologic presentation in acute myeloid leukemia (AML) with[J]. Europ J Haematol, 2010, 84(2):180-182.
[31]
Ikezoe T, Kojima S, Furihata M, et al. Expression of p-JAK2 predicts clinical outcome and is a potential molecular target of acute myelogenous leukemia[J]. Int J Cancer, 2011, 129(10):2512-2521.
[32]
Kratz CP, Böll S, Kontny U, et al. Mutational screen reveals a novel JAK2 mutation, L611S, in a child with acute lymphoblastic leukemia[J]. Leukemia, 2005, 20(2):381-383.
[33]
Funakoshi-Tago M, Tago K, Sumi K, et al. The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice[J]. J Biol Chem, 2009, 284(19):12680-12690.
[34]
Li F, Guo HY, Wang M, et al. The effects of R683S (G) genetic mutations on the JAK2 activity, structure and stability[J]. Int J Biol Macromol, 2013, 60:186-195.
[35]
Wu QY, Guo HY, Li F, et al. Disruption of E627 and R683 interaction is responsible for B-cell acute lymphoblastic leukemia caused by JAK2 R683G(S) mutations[J]. Leuk Lymphoma, 2013, 54(12):2693-2700.
[36]
Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia[J]. Proc Natl Acad Sci U S A, 2009, 106(23):9414-9418.
[37]
Chen IM, Harvey RC, Mullighan CG, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia:a Children's Oncology Group study[J]. Blood, 2012, 119(15):3512-3522.
[38]
Buitenkamp TD, Pieters R, Gallimore NE, et al. Outcome in children with Down's syndrome and acute lymphoblastic leukemia:role of IKZF1 deletions and CRLF2 aberrations[J]. Leukemia, 2012, 26(10):2204-2211.
[39]
Haan C, Behrmann I, Haan S. Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases[J]. J Cell Mol Med, 2010, 14(3):504-527.
[40]
Zhong Y, Wu J, Ma R, et al. Association of Janus kinase 2 (JAK2) polymorphisms with acute leukemia susceptibility[J]. Int J Lab Hematol, 2012, 34(3):248-253.
[41]
Nahajevszky S, Andrikovics H, Batai A, et al. The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia[J]. Haematologica, 2011, 96(11):1613-1618.
[42]
Verstovsek S, Silver RT, Talpaz M, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis[J]. NEJM, 2012, 366(9):799-807.
[43]
Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse[J]. Blood, 2011, 117(12):3294-3301.
[44]
Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis[J]. Leukemia, 2013, 27(6):1322-1327.
[45]
Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a sSelective JAK2 inhibitor, inmyelofibrosis[J]. J Clin Oncol, 2011, 29(7):789-796.
[46]
Weisberg E, Liu Q, Nelson E, et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3- positive AML:synergism between FLT3 inhibitors, dasatinib/ multi-targeted inhibitors and JAK inhibitors[J]. Leukemia, 2012, 26(10):2233-2244.
[47]
Hart S, Goh KC, Novotny-Diermayr V, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies[J]. Leukemia, 2011, 25(11):1751-1759.
[48]
Novotny-Diermayr V, Hart S, Goh KC, et al. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML[J]. Blood Cancer J, 2012, 2(5):e69.
[49]
Verstovsek S, Silver RT, Talpaz M, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis[J]. NEJM, 2012, 366(9):799-807.
[50]
Barosi G, Zhang MJ, Peter GR. Does ruxolitinib improve survival of persons with MPN-associated myelofibrosis? Should it?[J]. Leukemia, 2014, 28(11):2267-2270.
[51]
Kesarwani M, Huber E, Azam M. Overcoming AC220 resistance of FLT3-ITD by SAR302503[J]. Blood Cancer J, 2013, 3:e138.
[52]
Verstovsek S, Tam CS, Wadleigh M, et al. Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor[J]. Leukemia Res, 2014, 38(3):316-322.
Cook AM, Li L, Ho Y, et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells[J]. Blood, 2014, 123(18):2826-2837.
[55]
Abdel-Aziz MM. Clinical significance of serum p53 and epidermal growth factor receptor in patients with acute leukemia[J]. Asian Pac J Cancer Prev, 2013, 14(7):4295-4299.
[56]
DeAngelo DJ, Neuberg D, Amrein PC, et al. A phase II study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia[J]. Leuk Res, 2014, 38(4):430-434.
[57]
Lainey E, Wolfromm A, Sukkurwala AQ, et al. EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D[J]. Cell Cycle, 2014, 12(18):2978- 2991.
