Recently, Bellanné-Chantelot and co-workers have studied a series of 72 families with Philadelphia-chromosome-negative chronic myeloproliferative disorders (Ph− CMPD) and found constant JAK2V617F mutation in 22 families.1 Although the distribution of Ph− CMPD phenotypes within families suggested autosomal-dominant inheritance with incomplete penetrance, the absence of the JAK2V617F mutation both in purified B/T lymphocytes in 13 unrelated patients and variable ratios of the mutant allele in peripheral leukocytes indicated that JAK2V617F was acquired and not transmitted by germ line.1
We present a case of familial Ph− CMPD with JAK2V617F mutation revealing different patterns of hematopoietic lineage involvement. The somatic nature of the mutation could be proven by comparison with non-hematopoietic tissues.
An 80-year-old woman suffered from polycythemia vera (PV) since 11 years, and recently PV was also diagnosed in her 49-year-old daughter. Diagnosis was confirmed by histological examination of bone marrow (BM) biopsies, detection of JAK2V617F in BM2 and elevated CD177 levels in peripheral blood (PB) granulocytes.3, 4 Cytogenetic and array-based comparative genomic hybridization analyses were performed as described.5 No aberrations were detected. Subsequently, JAK2V617F mutant gene dosage was quantified with the PCR-based pyrosequencer6 in separated hematopoietic lineages. Purification was performed either by laser microdissection of BM cells6 or by flow cytometric cell sorting of PB CD15+ granulocytes, CD19+ B and CD3+ T lymphocytes.6 As a germ line control, we used laser-microdissected gastric epithelial cells from the mother and buccal cells from the daughter. Analysis of JAK2V617F-mutated alleles in laser-microdissected BM cells of the mother revealed 78% for erythropoietic and 20% for megakaryocytic cells. Analysis of the daughter's cells rendered similar values (51 and 21%, respectively) (Figure 1a). Erythropoietic islands were identified by immunohistochemical labeling of hemoglobin (Figure 1b).
Interestingly, the daughter's CD15+ cells were clonal, as evidenced by human androgen receptor gene assay (HUMARA),3 but were devoid of the JAK2V617F mutation7 (Figure 1a). By contrast, the maternal CD15+ cells showed 81% JAK2V617F alleles. In addition, the mother's granulocytes exhibited a ∼4 times higher CD177 level than the daughter's, resembling sporadic PV.3 Epithelial cells and lymphoid cells revealed a germ line configuration of JAK2.
This case of familial PV sheds light on several aspects of the still incompletely understood biology of the JAK2V617F mutation in hematopoietic cells. Although familial, it is obviously not transmitted by germ line, as evidenced for the first time, by comparison with non-hematopoietic cells. The pattern of lineage involvement in familial JAK2V617F mutation may differ among diseased family members. Furthermore, the case illustrates that granulocytes in PV may be clonal, but they are not affected by the JAK2V617F mutation.7, 8 Despite the absence of the JAK2V617F mutation, the granulocytes of the daughter were enhanced in number and exhibited an exaggerated CD177 expression typically found in PV.3 Non-germ line transmission as well as abnormal and clonal but unmutated granulopoiesis may be considered as an indication that, at least in a subfraction of Ph− CMPD, the JAK2V617F mutation constitutes a secondary event to still unknown primary genetic aberrations, which potentially convey an inherited predisposition for hematopoietic cells to acquire the JAK2V617F mutation.
Bellanné-Chantelot C, Chaumarel I, Labopin M, Bellanger F, Barbu V, De Toma C et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108: 346–352.
Bock O, Busche G, Koop C, Schroter S, Buhr T, Kreipe H . Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from chronic myeloproliferative disorders. J Mol Diagn 2006; 8: 170–177.
Steimle C, Lehmann U, Temerinac S, Goerttler PS, Kreipe H, Meinhardt G et al. Biomarker analysis in polycythemia vera under interferon-alpha treatment: clonality, EEC, PRV-1, and JAK2 V617F. Ann Hematol 2007; 86: 239–244.
Bock O, Serinsoz E, Neusch M, Schlue J, Kreipe H . The polycythaemia rubra vera-1 gene is constitutively expressed by bone marrow cells and does not discriminate polycythaemia vera from reactive and other chronic myeloproliferative disorders. Br J Haematol 2003; 123: 472–474.
Steinemann D, Skawran B, Becker T, Tauscher M, Weigmann A, Wingen L et al. Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization. Clin Gastroenterol Hepatol 2006; 4: 1283–1291.
Hussein K, Brakensiek K, Ballmaier M, Bormann M, Gohring G, Buhr T et al. B-CLL developing in a patient with PV is not affected by V617F mutation of the Janus kinase 2. Eur J Haematol 2006; 77: 539–541.
Zehentner BK, Loken MR, Wells DA . JAK2(V617F) mutation can occur exclusively in the erythroid lineage and be absent in granulocytes and progenitor cells in classic myeloproliferative disorders. Am J Hematol 2006; 81: 806–807.
Kralovics R, Teo S-S, Li S, Theocharides A, Buser AS, Tichelli A et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108: 1377–1380.
This study was supported by grants from Deutsche Krebshilfe, Dr Mildred Scheel Stiftung 10-2191 (OB, HK) and Deutsche Forschungsgemeinschaft –DFG BO 1954/1-1 (OB, HK).
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Hussein, K., Bock, O., Ballmaier, M. et al. Familial polycythemia vera with non-germ line JAK2V617F mutation sparing the abnormal and clonal granulopoiesis. Leukemia 21, 2566–2568 (2007). https://doi.org/10.1038/sj.leu.2404846
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