Screening of JAK2 V617F mutation in multiple myeloma

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Jul 27, 2006 - 1Department of Pathology and Anatomical Sciences, Ellis. Fischel Cancer Center, University of Missouri School of. Medicine, Columbia, MO ...
Letters to the Editor

1912 CD10 showed no methylation, but this was not absolute. This suggests that CD10 methylation might play a role in lymphoid malignancies by silencing CD10 expression, but this does not occur in all cases, and in fact does not prove a cause and effect relationship. Results of this study suggest that the biphasic pattern of CD10 expression in normally differentiating B cells is not controlled by methylation of the CD10 promoter. The expression of CD10 in Mec1 cells is restored after treatment with the combination of a demethylating agent and a histone deacetylase inhibitor, but neither alone; this suggests epigenetic modifications in the silencing of CD10 in this cell line and perhaps in B-cell malignancies, but requires further investigations for complete elucidation.

Acknowledgements This work was supported by the National Cancer Institute grants CA100055 and CA097880 (CW Caldwell). KH Taylor and J Liu contributed equally to this work. We also appreciate the helpful editorial work of Ms Angel Surdin.

KH Taylor1, J Liu1, J Guo1, JW Davis2, H Shi1 and CW Caldwell1 1 Department of Pathology and Anatomical Sciences, Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, USA and

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Department of Statistics, Department of Health Management and Informatics, University of Missouri School of Medicine, Columbia, MO, USA E-mail: [email protected]

References 1 Jaffe ES, Harris NL, Stein H, Vardiman JE. World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001, pp 109–111. 2 Cutrona G, Tasso P, Dono M, Roncella S, Ulivi M, Carpaneto EM et al. CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL. Br J Cancer 2002; 86: 1776–1785. 3 Laird PW. Cancer epigenetics. Hum Mol Genet 2005; 14 (Spec No 1): R65–R76. 4 Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–428. 5 Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM et al. DNA methylation of multiple promoterassociated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 2217–2224. 6 Caldwell CW, Patterson WP. Relationship between CD45 antigen expression and putative stages of differentiation in B-cell malignancies. Am J Hematol 1991; 36: 111–115. 7 Shi H, Guo J, Duff D, Rahmatpanah F, Chitima-Matsuga R, Al-Kuhlani M et al. Discovery of novel epigenetic markers in non-Hodgkin’s lymphoma. Carcinogenesis 2006, in press.

Screening of JAK2 V617F mutation in multiple myeloma

Leukemia (2006) 20, 1912–1913. doi:10.1038/sj.leu.2404332; published online 27 July 2006

Janus tyrosine kinase (JAK) tyrosine kinases are important mediators of cellular signals between cytokines, receptors and effector proteins. They have seven structural domains ‘JAK homology regions’. (JH1–JH7), in particular JH1 and JH2: JH1 has kinase activity, whereas JH2 has a negative-regulatory function on JH1. Recently, a somatic mutation in exon 12 of JAK2 has been described in myeloproliferative diseases: Philadelphia chromosome negative as polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF),1 and more recently this mutation has also been investigated in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), atypical chronic myeloid leukemia (aCML) (BCR-ABL negative), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).2,3 This point mutation results in a substitution of valine for phenylalanine at position 617 (V617F) in the JH2 domain and leads to constitutive tyrosine phosphorylation and cytokine hypersensitivity. Neoplastic cells can be heterozygous for the mutation or hemizygous if they have loss of heterozygosity of 9p chromosome, where JAK2 is located. JAK2 V617F mutation was identified in 81% (range, 65–97%) of patients with PV, 39% (23–57%) with ET and 43% (35–50%) with idiopatic myelofibrosis (IMF). It was detected, also, in a subset of CMML/aCML, and MDS but not in B-ALL, T-ALL or CLL.2,3 Alterations of JAK/signal transducers and activators of transcription (STAT) signaling molecules with a constitutive activation of STATs have been reported for several lymphoma as Leukemia

in primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin’s lymphoma (cHL), and screening for the presence of the mutation has revealed the absence of JAK2 V617F from all cell lines, PMBLs and cHLs.4 Other authors investigated the presence of JAK2 V617F mutation in cancers and myeloid malignancies other than the classic myeloproliferative diseases and they found that this mutation is uncommon in non-hematologic cancers and in myeloid malignancies other than the classic BCR/ABL-negative myeloproliferative diseases.5 We investigated the presence of JAK2 V617F mutation in multiple myeloma (MM), a B-cell neoplastic disease characterized by bone marrow (BM) infiltration from malignant plasma cells, which secrete monoclonal immunoglobulin fragments. Although several parameters such as b2-microglobulin, serum creatinine, hemoglobin, calcium levels or cytogenetics abnormalities have been taken into account as predictive factors of the outcome of patients affected by MM, the molecular features of this disease remain still unclear. Cytokines of interleukin-6 (IL-6) family, which activate the signals transducers gp130, are major survival and growth factors in vivo and in vitro for MM cells. The signal transduction of gp130 involves the JAKs JAK1, JAK2 and TyK2, and then the downstream effectors comprising the STAT3 and mitogen-activated protein kinase (MAPK) pathways.6 Activation of both the STAT and Ras-MAPK pathways is necessary for cell proliferation. Some authors found that an inhibitor of JAK2, AG490, suppressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited.6 Other authors demonstrated that the IL-6 activation of JAK2 is not involved in

Letters to the Editor

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in MM, a comprehensive mutational screening of its coding exons is warranted.

A Fiorini, G Farina, G Reddiconto, M Palladino, E Rossi, T Za, L Laurenti, S Giammarco, P Chiusolo, G Leone and S Sica Institute of Hematology, Catholic University, Rome, Italy E-mail: [email protected] Figure 1 Allele-specific polymerase chain reaction (PCR) for the V617F mutation. The 364-bp band serves as an internal control. The 203-bp band indicates the presence of the mutation. Lanes 2–8, MM samples; lane 1, positive control.

References

the activation of IGF-1 receptor-mediated signals in an MM cell line.7 To detect the JAK2 V617F mutation, we performed allelespecific polymerase chain reaction,1 using genomic DNA from peripheral blood samples of 93 consecutive patients affected by MM diagnosed according to Durie’s criteria. All samples were collected after informed consent from 2002 till 2005 and were mostly taken at diagnosis. We used peripheral blood samples because of the clonal relationship, termed clonotypic, demonstrated between B-lineage blood cells and BM plasma cells in patients with MM. These B cells are morphologically and functionally distinct from plasma cells. They are CD19 þ , CD11b þ and CD34 þ cells that express mRNA encoding IgH, CD19 and CD34. This clonotypic B-cell subset has properties consistent with malignant status.8 Patients’characteristics were as follows: median age at diagnosis 66 years (range 35–88), M/F 51/42, immunoglobulin (Ig)G 53/93 (57%), IgA 28/93 (30.1%), micromolecular 9/93 (9.7%), IgD 2/93 (2.1%), IgM 1/93 (1.1%), stage I 10/93 (10.8%), stage IIA 35/93 (38%), stage IIB 2/93 (2.1%), stage IIIA 44/93 (47%) and stage IIIB 2/93 (2.1%). All 93 MM samples analyzed were wild type for the JAK2 V617F mutation and presented the only internal control on electrophoresis agarose gel (364 bp) and not the 203 bp product, indicative of JAK2 mutation V617F (Figure 1). Thus, the mutation of JAK2 V617F is absent in MM and we can suggest that JAK2 mutation V617F does not play a role in the pathogenesis of MM. Given the importance of JAK2 activation

1 Baxter EJ, Scott LM, Campbell PJ, East C, Fourclas N, Swanton S, et al., Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061. 2 Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E et al. The JAK2 activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukaemia, but not in acute lymphoblastic leukaemia or chronic lymphocytic leukaemia. Blood 2005; 106: 3377–3379. 3 Sulong S, Case M, Minto L, Wilkins B, Hall A, Irving J. The V617F mutation in JAK2 is not found in childhood acute lymphoblastic leukemia. BrJ Haematol 2005; 130: 964–972. 4 Melzner I, Weniger MA, Menz CK, Moller P. Absence of the JAK2 V617F activating mutation in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Leukemia 2006; 20: 157–158. 5 Scott LM, Campbell PJ, Baxter EJ, Todd T, Stephens P, Edkins S et al. The V617F JAK2 mutation is uncommon in cancers and myeloid malignancies other than the classic myeloproliferative disorders. Blood 2005; 106: 2920–2921. 6 De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B. JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogenactivated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol 2000; 109: 823–828. 7 Abroun S, Ishikawa H, Tsuyama N, Liu S, Otsuyama KM, Zheng X et al. Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-1 in myeloma cells that highly express IL-6 receptor alpha. Blood 2004; 103: 2291–2298. 8 Bergsagel PL, Masellis S, Szczepek A, Mant MJ, Belch AR, Pilarski LM. In multiple myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells expressing CD38, CD56 and monotypic immunoglobulin light chain. Blood 1995; 85: 436–447.

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