ConcomitantJAK2V617F-positive polycythemia vera and B-cell chronic lymphocytic leukemia in three patients originating from two separate hematopoietic stem cells

Abstract

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, 1 was homozygous, and 2 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 utilized different active X-chromosomes (see Table 1). Table 1 The JAK2 V617F mutation and X chromosome clonality analyses in myeloid and lymphoid lineages. We have analyzed T- and B-lymphocytes, granulocytes, monocytes and platelets from three such female patients for specific CD markers of lineage commitment and ... 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/pre-leukemic 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 utilized different active X-chromosomes, i.e. 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 hematopoietic stem cells 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 MPN(13, 14).