Concomitant <i>JAK2</i> V617F‐positive polycythemia vera and B‐cell chronic lymphocytic leukemia in three patients originating from two separate hematopoietic stem cells
Authors: Sabina Swierczek, Jitka Nausova, Jaroslav Jelinek, Enli Liu, Paul Roda, Jana Kucerova, Marie Jarosova, Helena Urbankova, Karel Indrak, Josef T. Prchal, Vladimir Divoky
Journal: American Journal of Hematology (2012)

The simultaneous occurrence of polycythemia vera (PV) and chronic lymphocytic leukemia (CLL) is a rare event that offers a possibility to study their common origin. PV originates from self-renewing hematopoietic stem cells (HSC) with both lymphoid and myeloid potential [1-3]. It has been reported that CLL also originates from self-renewing HSC with a potential for both lymphoid and myeloid differentiation 4, 5. We report three females with concomitant CLL and PV whose X-chromosome inactivation patterns of the neoplastic cells revealed that granulocytes/platelets and B-lymphocytes used different X-chromosome alleles. These data indicate that both PV and CLL have arisen independently and from different HSC. Rare concurrent PV and CLL patients have been reported [6-8]. In these patients, the JAK2 V617F mutation, a marker of PV, was absent in the CLL B-cell lineage. These earlier findings did not rule out a possibility that these two distinct hematological disorders had not arisen from the same primitive HSC that was the subject of somatic mutation(s) leading to two different clonal diseases. We studied three such subjects: Patient 1, a 79-year-old Caucasian female had PV diagnosed in 1998 and CLL in 2000. Patient 2, a 67-year-old African American female was diagnosed with PV in 1997 and with B-CLL in 2001. Patient 3, is a 78-year-old Caucasian female whose PV and CLL were diagnosed over 10 years ago. The PV diagnoses were supported by growth of endogenous erythroid colonies (EECs), a hallmark of PV, and the presence of JAK2 V617F mutation in granulocytes. The results are summarized in Table 1. Patient 1 had a JAK2 V617F allelic burden of 50% in the PV clone (granulocytes and monocytes) but not in T- or B-lymphocytes. We also investigated the JAK2 V617F-positive cells by genotyping individual EEC colonies; 10 EEC were heterozygous, one was homozygous, and two were without the JAK2 V617F mutation, consistent with an earlier finding that the JAK2 mutation in PV is not the primary disease-initiating event [9-11]. Similarly, Patients 2 and 3 had the JAK2 V617F mutation in their granulocytes, but none in CD19-positive B- and CD-3-positive T-cells. PV and CLL lineages of all three patients used different active X-chromosomes (see Table 1). Thus, the hematopoietic neoplasms in these individuals with CLL and PV arose from distinct HSC. Earlier reports did not rule out the possibility that these disorders had not arisen from the same HSC that was the subject of further somatic mutation(s) leading to a clone (pre-JAK2 V617F clone/preleukemic CLL clone) that preceded the subsequent JAK2 V617F PV mutation. This possibility is now conclusively ruled out by the fact that the PV and CLL clones of these females used different active X-chromosomes, that is, their CLL and PV arose from separate HCS. Nevertheless, it is well possible that the presence of as yet-undefined germ-line mutation(s) may predispose all HSC to somatic events leading to two different hematological malignancies. Such evidence exists for familial clustering of PV and other myeloproliferative disorders 12, and is also suggested from the increased risk of lymphoproliferative neoplasms in myeloproliferative neoplasms 13, 14. The authors like to thank Ester Mejstrikova, Ondrej Hrusak, and Sona Pekova (Prague, Czech Republic) for assistance with some experiments. Sabina Swierczek1 Jitka Nausova2 Jaroslav Jelinek3 Enli Liu4 Paul Roda5 Jana Kucerova2 Marie Jarosova6 Helena Urbankova6 Karel Indrak6 Josef T. Prchal1 Vladimir Divoky2,6 1Division of Hematology, Department of Medicine, University of Utah, School of Medicine and VAH, Salt Lake City, Utah 84132; 2Department of Biology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic; 3Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; 4Texas Children's Cancer Center; and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030; 5Geisinger Hazleton Cancer Center, Hazleton, Pennsylvania 18201; 6Department of Hemato-oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 77520 Olomouc, Czech Republic Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.