JAK2V617F-positive polycythemia vera and Philadelphia chromosome-positive chronic myeloid leukemia: one patient with two distinct myeloproliferative disorders

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Polycythemia vera (PV), essential thrombocythemia and myelofibrosis with myeloid metaplasia are myeloproliferative disorders whose diagnosis requires the negativity of BCR–ABL rearrangement. A gain-of-function mutation at codon 617 (V617F) of the janus kinase 2 (JAK2) gene has been discovered in BCR–ABL-negative myeloproliferative disorders.1 Conversely, no JAK2 mutation has been found in Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML).2 Nevertheless, some rare cases of patients harboring both a BCR–ABL rearrangement and a JAK2V617F mutation have been reported in the literature, their coexistence appearing during the evolution of the disease.3, 4, 5 Recently, Bornhäuser et al.6 described concurrent JAK2V617F mutation and BCR–ABL translocation in one case of myelofibrosis with myeloid metaplasia at diagnosis. Here, we report concomitant BCR–ABL rearrangement and JAK2V617F mutation at the initial presentation of a CML and a PV in a single patient.

A 64-year-old man presented with pruritus, ruddy face and splenomegaly. The hemogram showed an elevated white blood cell count (15.3 G/l), including myelocytes 5%, segmented neutrophils 73%, eosinophil granulocytes 3%, basophil granulocytes 1%, lymphocytes 11% and monocytes 7%, a very high hemoglobin level (24.6 g dl−1) and a normal platelet count (380 G/l). Arterial blood oxygen studies were normal and the serum erythropoietin level was below the reference range. Bone marrow morphologic analysis showed normal cellularity without granulocytic hyperplasia. The number of megakaryocytes was normal. Bone marrow cytogenetic analysis revealed 10 Ph-chromosome-positive metaphases, 3 metaphases with deletion of the Y chromosome and 8 normal metaphases out of 21 metaphases analysed. Fluorescence in situ hybridization analysis using the BCR–ABL extra signal probe (Vysis, Woodcreek, IL, USA) confirmed the BCR–ABL fusion on metaphases (Figure 1a) and showed a low percentage of positive interphase nuclei (21%). Molecular analysis performed on peripheral blood leukocytes showed a BCR–ABL transcript e14a2 (b3a2) at a relatively low level (ratio BCR–ABL/ABL: 10%). Moreover, a homozygous JAK2V617F mutation was detected on genomic DNA by single-nucleotide polymorphism genotyping assays using real-time PCR-based mutation detection (TaqMan ABI PRISM 7000, Applied Biosystems, Foster City, CA, USA), as described previously.7 Semisolid clonogenic assay of BFU-E (burst-forming units-erythroid) showed the presence of endogenous erythroid colony formation without erythropoietin. Interestingly, fluorescence in situ hybridization analysis with BCR–ABL extrasensitive probe (Vysis) performed on these endogenous erythroid colonies revealed no BCR–ABL fusion (Figure 1b), demonstrating that the PV and the CML clones were distinct.

Figure 1

Fluorescence in situ hybridization analysis. (a) Bone marrow FISH analysis using BCR–ABL ES and CEP X/Y probes (Vysis) showing the BCR–ABL-specific fusion signal in a representative metaphase. The deletion of the Y chromosome was not observed on this metaphase. The BCR–ABL fusion was associated with an ABL-BCR deletion. (b) FISH analysis using BCR–ABL ES probe (Vysis) performed on endogenous erythroid colonies revealed no BCR–ABL fusion. ES, extra signal; FISH, fluorescence in situ hybridization.

The patient was phlebotomized and imatinib mesylate (IM) was initiated at a daily dose of 400 mg. IM was well tolerated and interruption of IM treatment or dose reduction was not required. A complete blood count and hemogram were checked every 4 weeks during IM therapy. The follow-up of the Ph-positive clone was performed by bone marrow karyotype and real-time quantitative PCR on peripheral blood leukocytes. A complete cytogenetic response could be achieved after 6 months of IM therapy. After 9 months of IM therapy, the patient achieved a complete and persistent molecular remission for BCR–ABL (Figure 2). In contrast, IM therapy had no effect on hematocrit in this patient and venesections had to be performed every 6–8 weeks to maintain hematocrit under 48%. Furthermore, sequential evaluation of the JAK2V617F allele showed the persistence of a high level of JAK2-mutated allele. Thus, the progressive decrease in the expression of the Ph-positive clone was associated with an expansion of the JAK2V617F-positive clone, suggesting that IM at a daily dose of 400 mg had no inhibitory effect on the JAK2-mutated clone in this patient.

Figure 2

Sequential follow-up of minimal residual disease. The MRD monitoring is performed by quantification of BCR–ABL fusion transcript by RQ-PCR. At diagnosis, the ratio BCR–ABL/ABL was relatively low (10%). After 9 months of IM therapy, the patient achieved a complete and persistent molecular remission. IM, imatinib mesylate; MRD, minimal residual disease; RQ-PCR: real-time quantitative-PCR.

Few cases showing the coexistence in a single patient of a CML with another myeloproliferative disorders have been reported so far.3, 4, 5, 6, 8 Inami et al.5 reported one case of a Ph-positive CML patient who developed a JAK2V617F-positive PV several years after the initial diagnosis of CML, whereas Wahlin et al.8 reported the emergence of Ph-positive CML during the evolution of an essential thrombocythemia treated by hydroxyurea. Besides, Hussein et al.4 reported one case of myelofibrosis with myeloid metaplasia evolving during the treatment by IM of a CML disease with a t(9;22) translocation coexisting with a JAK2V617F mutation. Recently, concurrent JAK2V617F mutation and BCR–ABL rearrangement have been described within committed myeloid progenitors in myelofibrosis with myeloid metaplasia.6 In this case, molecular analysis demonstrated that the JAK2V617F mutation is present in all the myeloid cells, while the BCR–ABL fusion is not detected in erythroid progenitors. These findings support the idea that BCR–ABL is a secondary event, like in the case reported by Bornhäuser et al.6 Similarly, we and others reported some cases with a secondary Ph-chromosome acquired during the course of a myelodysplastic syndrome.9, 10

In summary, we confirmed that BCR–ABL rearrangement and JAK2V617F mutation may occur concomitantly in hematopoietic cells of a single patient at initial presentation. After the onset of IM therapy, the CML clone became undetectable, while the JAK2V617F-mutated clone continued to grow, suggesting that the PV erythroid progenitors were not inhibited by a 400 mg daily dose of IM. To note that a specific time- and dose-dependant effect of IM on FDCP cell line expressing the JAK2V617F mutant has been reported.11 In this case, we did not increase the dose of IM to reduce the hematocrit, but IM therapy was ineffective on the PV clone, as described previously.5


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This work was supported by the Fondation de France (Comité Leucémie) and the North West Cancéropole (Axe Onco-Hématologie).

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Correspondence to C Preudhomme.

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Cambier, N., Renneville, A., Cazaentre, T. et al. JAK2V617F-positive polycythemia vera and Philadelphia chromosome-positive chronic myeloid leukemia: one patient with two distinct myeloproliferative disorders. Leukemia 22, 1454–1455 (2008) doi:10.1038/sj.leu.2405088

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