Alterations of JAK/STAT signaling molecules have been reported for several lymphomas including primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL), where constitutive activation of STATs was found.1, 2 PMBL is a rather rare disease, however, there is increasing evidence that it is closely related to the far more frequent cHL.3 One common characteristic of these two entities is a frequent gain of 9p24 involving JAK2 which consequently has attracted considerable attention as potential trigger in the pathogenesis of these lymphomas. Recent publications revealed a substantial role for a gain of function mutation of JAK2 that results in constitutive activation of the tyrosine kinase, phosphorylation of STAT5, and expression of genetic markers in diverse myeloproliferative disorders, such as polycythemia vera, acute and chronic myeloid leukemia.4, 5, 6, 7 However, it was not found in acute and chronic lymphocytic leukemia.5
The underlying G to T transversion at nucleotide 1849 in exon 12 of JAK2 is located in the JH2 pseudo-kinase domain of JAK2 and leads to a substitution of valine to phenylalanine at position 617 (V617F).7 This region is involved in the auto-inhibition of its kinase activity and results in constitutive JAK2 activation.7 The wild-type sequence of exon 12 provides a specific restriction site for the endonuclease BsaXI, however, the nucleotide exchange of guanine to thymindine abolishes this restriction site preventing cleavage of the amplified exon 12 including sequence. Taking advantage of this, we screened genomic DNA of microdissected Hodgkin/Reed–Sternberg (HRS) cells of 16 cHLs, 20 PMBLs, five cHL (L428, L1236, HDLM-2, KM-H2, and L540) and two PMBL cell lines (MedB-1 and Karpas1106) for presence of the activating V617F mutation in the JAK2 gene by site-specific restriction analysis (Figure 1a).
Our results demonstrate the absence of the G → T mutation in both alleles of JAK2 since BsaXI completely cleaved the PCR product yielded from DNA of all cell lines, PMBLs, and cHLs (Figure 1b).
Nevertheless, there is evidence for constitutive JAK/STAT activity in PMBL and cHL. We lately found mutations in SOCS-1 (suppressor of cytokine signaling-1), a negative regulator of this pathway. In PMBL lines MedB-1 and Karpas1106, SOCS-1 defects prolonged activity of phospho-JAK2 leading to constitutive STAT5 activation.8, 9 Moreover, in neoplastic cells of cHLs SOCS-1 mutations were equally frequent and were associated with nuclear accumulation of phosph-STAT5 indicating constitutive STAT5 activity.10
Our analysis of JAK2 excluded the V617F mutation in cHL and PMBL. We conclude that this activating mechanism of JAK2 is not operative in these lymphomas. Hence, attention reconcentrates on other JAK/STAT activating mechanisms, for example, mutations or silencing of negative regulators like SOCS-1 and/or protein-tyrosine phosphatases.
Kube D, Holtick U, Vockerodt M, Ahmadi T, Haier B, Behrmann I et al. STAT3 is constitutively activated in Hodgkin cell lines. Blood 2001; 98: 762–770.
Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland ML, Le Gouvello S, Gaulard P et al. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood 2004; 104: 543–549.
Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003; 198: 851–862.
Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both ‘atypical’ myeloproliferative disorders and myelodysplastic syndromes. Blood 2005; 106: 1207–1209.
Levine RL, Loriaux M, Huntly BJ, Loh M, Beran M, Stoffregen E et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005 Aug 4; [E-pub ahead of print] PMID: 16081687 [PubMed – as supplied by publisher].
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.
Melzner I, Bucur AJ, Bruderlein S, Dorsch K, Hasel C, Barth TF et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 2005; 105: 2535–2542.
Melzner I, Bucur AJ, Weniger MA, Brüderlein S, Dorsch K, Hasel C et al. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein. Int J Cancer, (Published Online 14 Nov 2005, doi:10.1002/ijc.21485).
Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene, in press.
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Melzner, I., Weniger, M., Menz, C. et al. Absence of the JAK2 V617F activating mutation in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Leukemia 20, 157–158 (2006) doi:10.1038/sj.leu.2404036
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