Int J Hematol (2014) 99:87–90 DOI 10.1007/s12185-013-1480-z
CASE REPORT
Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation Weiyi Xu • Baode Chen • Xiangmin Tong
Received: 14 March 2013 / Revised: 19 November 2013 / Accepted: 19 November 2013 / Published online: 30 November 2013 Ó The Japanese Society of Hematology 2013
Abstract The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms, but few cases of the JAK2 V617F mutation have been described in Philadelphia-positive chronic myeloid leukemia (CML) patients. Here, we report a 21-year-old female who presented with phenotype of CML in whom BCR-ABL transcript and JAK2V617F mutation co-occurred. These findings were determined through cytogenetic analysis, fluorescence in situ hybridization, and allele-specific (AS) PCR. The patient’s BCRABL transcript disappeared after 6 months of treatment with imatinib, while the JAK2V617F mutation remained positive. We discuss this case with reference to the current literature.
rearrangement of the ABL and BCR genes [1, 2]. The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), and is present in nearly 100 % of patients with polycythemia vera (PV) and in 50–60 % of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) [3]. Few cases of the JAK2 V617F mutation have been described in Philadelphia-positive CML patients [4– 10], but these cases raise questions about the clinical features and prognosis of CML patients with the coexistence of the JAK2 V617F mutation. Here, we report the case of a patient with concurrent expression of the BCR-ABL transcript and JAK2 V617F mutation; this case provides further insights into the biological meaning of this mutation in CML.
Keywords Chronic myeloid leukemia BCR-ABL JAK2 V617F mutation Case report Introduction Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22, which causes
W. Xu B. Chen Department of Clinical Laboratory, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China e-mail: [email protected] X. Tong (&) Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China e-mail: [email protected]
A 21-year-old female patient was admitted to our hospital in February 2010 with a 5-month history of gradual elevation of leukocyte and platelet counts. Physical examination revealed slight splenomegaly but no hepatomegaly, lymphadenopathy, or sternal tenderness. Laboratory investigations showed a hemoglobin (Hb) level of 133 g/L, leukocytosis (white cell count 73.2 9 109/L; differential leukocyte count neutrophil 54 %, lymphocyte 6 %, eosinophil 12 %, basophil 6 %, immature granulocyte 22 %), a platelet count of 440 9 109/L, and increased level of lactate dehydrogenase (LDH; 405 U/L). The neutrophil alkaline phosphatase score was 0. A bone marrow aspirate showed hypercellular marrow with increased number of granulocytes (72 % of nucleated cells) and a markedly increased number of megakaryocytes with normal platelet production.
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Fig. 1 Chronic myeloid leukemia with co-occurrence of BCR-ABL transcript and JAK2 V617F mutation. a Fluorescence in situ hybridization (FISH) using Spectrum green-labeled locus-specific identifier (LSI) ABL (9q34) and Spectrum orange-labeled LSI BCR (22q11.2) probes showing 1 yellow fusion signal, which indicates rearrangement between the ABL and BCR genes, as well as 1 orange and 2 green signals, indicating the original chromosomes 9 and 22. b JAK2 V617F mutation detected by allele-specific PCR. The upper 364-bp band
confirms the presence of amplifiable DNA. A second 203-bp band of varying intensity is clearly visible in the cases of Philadelphianegative myeloproliferative neoplasms (MPN) showing the mutation. Lane M marker, lane 1 negative control from normal donor DNA, lane 2 essential thrombocythemia (ET), lane 3 primary myelofibrosis (PMF), lane 4 polycythemia vera (PV), lane 5 patient sample, lane 6 another Philadelphia-positive CML patient
The cytogenetic analysis was performed by R-banding of the chromosomes in unstimulated bone marrow cells after culture for 24 h in RPMI 1640 (Sigma, Schnelldorf, Germany) supplemented with 20 % fetal bovine serum. At least 20 metaphases were analyzed, and the karyotype of our patient was 46, XX, t(9;22) (q34;q11) [11]/46, XX [8]. The remaining cells were subjected to fluorescence in situ hybridization (FISH) studies using the Vysis dual-color, dual-fusion, locus-specific identifier (LSI) BCR/ABL probe set (Abbott Molecular/Vysis, Des Plaines, IL), according to the manufacturer’s recommendations. The LSI BCR (22q11.2) probes were labeled with SpectrumOrange. For each hybridization assay, the BCR-ABL fusion signals were detected as 1 yellow BCR-ABL fusion signal, 2 green ABL signals, and 1 orange BCR signal in 65 % of the counted nuclei (Fig. 1a). In addition, real-time quantitative reverse transcription polymerase chain reaction confirmed the presence of BCR-ABL transcript (b2a2) at a high level (101 %). To detect the JAK2 V617F mutation, allele-specific (AS) PCR was performed [12]. This served as an internal PCR control for DNA integrity. Amplicons were separated by size using gel electrophoresis. The sensitivity of this technique could detect 3 % of cells [12]. One case each of PV, ET, and PMF was used as positive control, and DNA derived from a normal donor was used as the negative control. AS-PCR showed the 364-bp control band, but showed the mutant 203-bp band only in the presence of the JAK2 V617F mutation. No amplification was observed in the negative control and DNA derived from a typical Philadelphia-positive CML patient. The patient samples showed a 203-bp band similar to that observed in the samples of PV, ET, and PMF patients (Fig. 1B). These tests demonstrated that the patient, who had typical clinical features of Philadelphia-positive CML,
exhibited coexistence of the BCR-ABL transcript and JAK2 V617F mutation. After daily treatment with 400 mg imatinib for 20 days, the leukocytes and platelets of the patient had returned to normal levels (Hb 133 g/L, WBC 7.2 9 109/L, and platelets 326 9 109/L). After 6 months of imatinib treatment, the BCR-ABL transcript was undetectable, indicating a complete BCR-ABL molecular response. At the time of last follow-up in August 2013, the patient was in molecular remission of CML. However, repeated AS-PCR analyses still demonstrated positive JAK2 V617F mutation.
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Discussion CML is the common leukemia of adults, and constitutes about 15 % of all leukemias. This case report describes a rare coexistence of BCR-ABL fusion and JAK2 V617F mutation at diagnosis. A literature search revealed 17 welldocumented cases of CML with the concomitant presence of the BCR-ABL transcript and JAK2 V617F mutation in the same patients (Table 1). As shown in Table 1, there were 14 males and 4 females, with a median age of 51 years (range 21–70 years) at diagnosis. Similar to our patient, majority of patients usually had a typical CML phenotype, including leukocytosis and splenomegaly [4– 10], but showed abnormal features, such as a high hematocrit value [6]; moreover, upon bone marrow examination, they showed unusually large and clustered megakaryocytes [7] or showed predominant hyperplasia of the megakaryocytic lineage [10]. Most cases (11 out of 18) had presented BCR-ABL fusion gene and JAK2 V617F mutation simultaneously. The increasing sensitivity in the JAK2V617F mutation screening methods may allow to detect a higher frequency of patients expressing both mutations.
CML with the JAK2 V617F mutation
89
Table 1 Characteristics of reported cases of co-occurrence of BCR-ABL fusion transcript and JAK2 V617F mutation References
Age(years)/ sex
Interval (months)
Treatment
Follow-up after TKIs (months)
Outcomes (BCR-ABL/ JAK2 V617F mutation)
Kra¨mer et al. [5]
50/M
Simultaneous
Imatinib
96
CMR/positive
Inami et al. [6]
43/M
Simultaneous
Interferon-alpha, hydroxyurea, imatinib
60
CCyR/positive
Park et al. [14]. Park et al. [14]
58/M 36/M
Simultaneous Simultaneous
Hydroxyurea, dasatinib Hydroxyurea
7 NA
Good response/unknown NA Good response/positive
Conchon et al. [15]
52/F
Simultaneous
Hydroxyurea, imatinib
6
Hussein et al. [7].
64/M
Simultaneous
Phlebotomy, imatinib
9
CMR/positive
Hussein et al. [4].
55/M
Simultaneous
Imatinib
23
CMR/positive
Pastore et al. [16]
42/F
Simultaneous
Imatinib, dasatinib
96
MMR/positive
Pardini et al. [8]
67/M
Simultaneous
Imatinib
9
MMR/positive
Gattenlohner et al. [17]
67/M
Simultaneous
Imatinib
14
CMR/positive
Inokuchi et al. [11].
43/M
Simultaneous
Interferon-alpha, hydroxyurea, imatinib, dasatinib
156
CMR/negative
Ursuleac et al. [18]
61/M
84 (CML after MPN)
Hydroxyurea, Imatinib
24
CMR/positive
Hussein et al. [7].
32/M
40 (CML after MPN)
Anagrelide, hydroxyurea, imatinib
9
MMR/positive
Pingali et al. [19]
39/M
241 (CML after MPN)
Phlebotomy, imatinib, dasatinib, nilotinib
41
CMR/positive
Lee et al. [20]
53/M
118 (MPN after CML)
Interferon-alpha, imatinib, anagrelide, hydroxyurea
100
MMR/positive
Lee et al. [20]
60/F
30 (MPN after CML)
Imatinib, nilotinib, anagrelide
32
MMR/positive
Caocci et al. [10] Present case
70/M 21/F
NA Simultaneous
Interferon-alpha, imatinib Imatinib
6 42
CCyR/positive CMR/positive
CML chronic myeloid leukemia, M male, F female, TKIs Tyrosine kinase inhibitors, CMR complete molecular remission, CCyR complete cytogenetic remission, MMR major molecular response, MPN myeloproliferative neoplasm, NA not available
Interestingly, our patient achieved rapidly molecular remission of CML under the treatment with imatinib. As shown in Table 1, near all the patients treated with tyrosine kinase inhibitor had a good response of BCR-ABL positive clonal population of cells. We speculate that the JAK2V617F mutation have no influence on the clinical course of CML. That is important because in most cases, the clinical phenotype is consistent with CML. It suggests the contribution of BCR-ABL to disease progression is greater than that of JAK2 V617F. However, while imatinib treatment induced cytogenetic CML remission, the JAK2 V617F clone persisted in our patient, a phenomenon observed in most previous cases (Table 1). Of the 4 patients examined during a long-term follow-up, 3 patients developed PMF at a median time of 27 months (range 9–48 months) [4, 5, 8], and 1 showed progression to PV after 6 years [6]. In one case, the JAK2 V617F mutation was undetectable after the patient achieved a partial cytogenetic response to imatinib treatment [9]. Notably, in another interesting case, both the BCR-ABL fusion gene and the JAK2V617F mutation were not detectable after dasatinib
therapy [11]. It would be interesting to know if the new generation tyrosine kinase inhibitors or the possibility of combining treatment with tyrosine kinase and JAK2 inhibitors could be more effective for this rare clinical entity of CML. The biological relationships between the two molecular rearrangements BCR-ABL fusion gene and JAK2 V617F mutation in one patient are still unclear. In the present case, during the clinical course, the BCR-ABL decreased with the response of imatinib treatment, but the positivity of JAK2 V617F continued. As most cases presented the BCR-ABL and JAK2V617F mutation, we would speculate that the JAK2V617F and BCR-ABL were present in the two different clones. Recently, Wang et al. [13] reported that that both the JAK2 V617F mutation and BCR-ABL can occur concurrently in both CFU-GM and BFU-E. In summary, we reported a rare CML patient with the coexistence of BCR-ABL and the JAK2 V617F mutation. She had a good response of imatinib therapy. However, further molecular targeted therapeutic strategies have to be developed.
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90 Conflict of interest peting interests.
W. Xu et al. The authors declare that they have no com-
References 1. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3. 2. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550–4. 3. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673–83. 4. Hussein K, Bock O, Seegers A, Flasshove M, Henneke F, Buesche G, et al. Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation. Blood. 2007;109:4106–7. 5. Kramer A, Reiter A, Kruth J, Erben P, Hochhaus A, Muller M, et al. JAK2-V617F mutation in a patient with Philadelphiachromosome-positive chronic myeloid leukaemia. Lancet Oncol. 2007;8:658–60. 6. Inami M, Inokuchi K, Okabe M, Kosaka F, Mitamura Y, Yamaguchi H, et al. Polycythemia associated with the JAK2V617F mutation emerged during treatment of chronic myelogenous leukemia. Leukemia. 2007;21:1103–4. 7. Hussein K, Bock O, Theophile K, Seegers A, Arps H, Basten O, et al. Chronic myeloproliferative diseases with concurrent BCR-ABL junction and JAK2V617F mutation. Leukemia. 2008;22:1059–62. 8. Pardini S, Fozza C, Contini S, Rimini E, Ottaviani E, Amabile M, et al. A case of coexistence between JAK2V617F and BCR/ABL. Eur J Haematol. 2008;81:75–6. 9. Campiotti L, Appio L, Solbiati F, Ageno W, Venco A. JAK2V617F mutation and Philadelphia positive chronic myeloid leukemia. Leuk Res. 2009;33:e212–3. 10. Caocci G, Atzeni S, Orru N, Littera R, Culurgioni F, Marongiu F, et al. Response to imatinib in a patient with chronic myeloid leukemia simultaneously expressing p190(BCR-ABL) oncoprotein and JAK2V617F mutation. Leuk Res. 2010;34:e27–9. 11. Inokuchi K, Yamaguchi H, Tamai H, Dan K. Disappearance of both the BCR/ABL1 fusion gene and the JAK2V617F mutation with dasatinib therapy in a patient with imatinib-resistant chronic myelogenous leukemia. J Clin Exp Hematop. 2012;52:145–7.
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12. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365: 1054–61. 13. Wang X, Tripodi J, Kremyanskaya M, Blouin A, Roda P, Hoffman R, et al. BCR-ABL1 is a secondary event after JAK2V617F in patients with polycythemia vera who develop chronic myeloid leukemia. Blood. 2013;121:1238–9. 14. Park SH, Chi HS, Cho YU, Jang S, Park CJ, Kim DY, et al. Two cases of myeloproliferative neoplasm with a concurrent JAK2 (V617F) mutation and BCR/ABL translocation without chronic myelogenous leukemia phenotype acquisition during hydroxyurea treatment. Ann Lab Med. 2013;33:229–32. 15. Conchon MR, Costa JL, Novaes MM, Dorlhiac-Llacer PE, de Alencar Fischer Chamone D, Bendit I. Simultaneous detection of JAK2 V617F mutation and Bcr-Abl translocation in a patient with chronic myelogenous leukemia. Int J Hematol. 2008;88: 243–5. 16. Pastore F, Schneider S, Christ O, Hiddemann W, Spiekermann K. Impressive thrombocytosis evolving in a patient with a BCRABL positive CML in major molecular response during dasatinib treatment unmasks an additional JAK2V617F. Exp Hematol Oncol. 2013;2:24. 17. Gattenlohner S, Volker HU, Etschmann B, Einsele H, MullerHermelink HK. BCR-ABL positive chronic myeloid leukemia with concurrent JAK2(V617F) positive myelodysplastic syndrome/myeloproliferative neoplasm (RARS-T). Am J Hematol. 2009;84:306–7. 18. Ursuleac I, Colita A, Adam T, Jardan C, Ilea A, Coriu D. The concomitant occurrence of JAK2V617F mutation and BCR/ABL transcript with phenotypic expression—an overlapping myeloproliferative disorder or two distinct diseases?—case report. J Med Life. 2013;6:34–7. 19. Pingali SR, Mathiason MA, Lovrich SD, Go RS. Emergence of chronic myelogenous leukemia from a background of myeloproliferative disorder: JAK2V617F as a potential risk factor for BCR-ABL translocation. Clin Lymphoma Myeloma. 2009;9: E25–9. 20. Lee YJ, Moon JH, Shin HC, Seo JW, Han SA, Seo SK, et al. Two CML patients who subsequently developed features of essential thrombocythemia with JAK2-V617F mutation while in complete cytogenetic remission after treatment with imatinib mesylate. Int J Hematol. 2013;97:804–7.
CASE REPORT
Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation Weiyi Xu • Baode Chen • Xiangmin Tong
Received: 14 March 2013 / Revised: 19 November 2013 / Accepted: 19 November 2013 / Published online: 30 November 2013 Ó The Japanese Society of Hematology 2013
Abstract The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms, but few cases of the JAK2 V617F mutation have been described in Philadelphia-positive chronic myeloid leukemia (CML) patients. Here, we report a 21-year-old female who presented with phenotype of CML in whom BCR-ABL transcript and JAK2V617F mutation co-occurred. These findings were determined through cytogenetic analysis, fluorescence in situ hybridization, and allele-specific (AS) PCR. The patient’s BCRABL transcript disappeared after 6 months of treatment with imatinib, while the JAK2V617F mutation remained positive. We discuss this case with reference to the current literature.
rearrangement of the ABL and BCR genes [1, 2]. The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), and is present in nearly 100 % of patients with polycythemia vera (PV) and in 50–60 % of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) [3]. Few cases of the JAK2 V617F mutation have been described in Philadelphia-positive CML patients [4– 10], but these cases raise questions about the clinical features and prognosis of CML patients with the coexistence of the JAK2 V617F mutation. Here, we report the case of a patient with concurrent expression of the BCR-ABL transcript and JAK2 V617F mutation; this case provides further insights into the biological meaning of this mutation in CML.
Keywords Chronic myeloid leukemia BCR-ABL JAK2 V617F mutation Case report Introduction Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22, which causes
W. Xu B. Chen Department of Clinical Laboratory, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China e-mail: [email protected] X. Tong (&) Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China e-mail: [email protected]
A 21-year-old female patient was admitted to our hospital in February 2010 with a 5-month history of gradual elevation of leukocyte and platelet counts. Physical examination revealed slight splenomegaly but no hepatomegaly, lymphadenopathy, or sternal tenderness. Laboratory investigations showed a hemoglobin (Hb) level of 133 g/L, leukocytosis (white cell count 73.2 9 109/L; differential leukocyte count neutrophil 54 %, lymphocyte 6 %, eosinophil 12 %, basophil 6 %, immature granulocyte 22 %), a platelet count of 440 9 109/L, and increased level of lactate dehydrogenase (LDH; 405 U/L). The neutrophil alkaline phosphatase score was 0. A bone marrow aspirate showed hypercellular marrow with increased number of granulocytes (72 % of nucleated cells) and a markedly increased number of megakaryocytes with normal platelet production.
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Fig. 1 Chronic myeloid leukemia with co-occurrence of BCR-ABL transcript and JAK2 V617F mutation. a Fluorescence in situ hybridization (FISH) using Spectrum green-labeled locus-specific identifier (LSI) ABL (9q34) and Spectrum orange-labeled LSI BCR (22q11.2) probes showing 1 yellow fusion signal, which indicates rearrangement between the ABL and BCR genes, as well as 1 orange and 2 green signals, indicating the original chromosomes 9 and 22. b JAK2 V617F mutation detected by allele-specific PCR. The upper 364-bp band
confirms the presence of amplifiable DNA. A second 203-bp band of varying intensity is clearly visible in the cases of Philadelphianegative myeloproliferative neoplasms (MPN) showing the mutation. Lane M marker, lane 1 negative control from normal donor DNA, lane 2 essential thrombocythemia (ET), lane 3 primary myelofibrosis (PMF), lane 4 polycythemia vera (PV), lane 5 patient sample, lane 6 another Philadelphia-positive CML patient
The cytogenetic analysis was performed by R-banding of the chromosomes in unstimulated bone marrow cells after culture for 24 h in RPMI 1640 (Sigma, Schnelldorf, Germany) supplemented with 20 % fetal bovine serum. At least 20 metaphases were analyzed, and the karyotype of our patient was 46, XX, t(9;22) (q34;q11) [11]/46, XX [8]. The remaining cells were subjected to fluorescence in situ hybridization (FISH) studies using the Vysis dual-color, dual-fusion, locus-specific identifier (LSI) BCR/ABL probe set (Abbott Molecular/Vysis, Des Plaines, IL), according to the manufacturer’s recommendations. The LSI BCR (22q11.2) probes were labeled with SpectrumOrange. For each hybridization assay, the BCR-ABL fusion signals were detected as 1 yellow BCR-ABL fusion signal, 2 green ABL signals, and 1 orange BCR signal in 65 % of the counted nuclei (Fig. 1a). In addition, real-time quantitative reverse transcription polymerase chain reaction confirmed the presence of BCR-ABL transcript (b2a2) at a high level (101 %). To detect the JAK2 V617F mutation, allele-specific (AS) PCR was performed [12]. This served as an internal PCR control for DNA integrity. Amplicons were separated by size using gel electrophoresis. The sensitivity of this technique could detect 3 % of cells [12]. One case each of PV, ET, and PMF was used as positive control, and DNA derived from a normal donor was used as the negative control. AS-PCR showed the 364-bp control band, but showed the mutant 203-bp band only in the presence of the JAK2 V617F mutation. No amplification was observed in the negative control and DNA derived from a typical Philadelphia-positive CML patient. The patient samples showed a 203-bp band similar to that observed in the samples of PV, ET, and PMF patients (Fig. 1B). These tests demonstrated that the patient, who had typical clinical features of Philadelphia-positive CML,
exhibited coexistence of the BCR-ABL transcript and JAK2 V617F mutation. After daily treatment with 400 mg imatinib for 20 days, the leukocytes and platelets of the patient had returned to normal levels (Hb 133 g/L, WBC 7.2 9 109/L, and platelets 326 9 109/L). After 6 months of imatinib treatment, the BCR-ABL transcript was undetectable, indicating a complete BCR-ABL molecular response. At the time of last follow-up in August 2013, the patient was in molecular remission of CML. However, repeated AS-PCR analyses still demonstrated positive JAK2 V617F mutation.
123
Discussion CML is the common leukemia of adults, and constitutes about 15 % of all leukemias. This case report describes a rare coexistence of BCR-ABL fusion and JAK2 V617F mutation at diagnosis. A literature search revealed 17 welldocumented cases of CML with the concomitant presence of the BCR-ABL transcript and JAK2 V617F mutation in the same patients (Table 1). As shown in Table 1, there were 14 males and 4 females, with a median age of 51 years (range 21–70 years) at diagnosis. Similar to our patient, majority of patients usually had a typical CML phenotype, including leukocytosis and splenomegaly [4– 10], but showed abnormal features, such as a high hematocrit value [6]; moreover, upon bone marrow examination, they showed unusually large and clustered megakaryocytes [7] or showed predominant hyperplasia of the megakaryocytic lineage [10]. Most cases (11 out of 18) had presented BCR-ABL fusion gene and JAK2 V617F mutation simultaneously. The increasing sensitivity in the JAK2V617F mutation screening methods may allow to detect a higher frequency of patients expressing both mutations.
CML with the JAK2 V617F mutation
89
Table 1 Characteristics of reported cases of co-occurrence of BCR-ABL fusion transcript and JAK2 V617F mutation References
Age(years)/ sex
Interval (months)
Treatment
Follow-up after TKIs (months)
Outcomes (BCR-ABL/ JAK2 V617F mutation)
Kra¨mer et al. [5]
50/M
Simultaneous
Imatinib
96
CMR/positive
Inami et al. [6]
43/M
Simultaneous
Interferon-alpha, hydroxyurea, imatinib
60
CCyR/positive
Park et al. [14]. Park et al. [14]
58/M 36/M
Simultaneous Simultaneous
Hydroxyurea, dasatinib Hydroxyurea
7 NA
Good response/unknown NA Good response/positive
Conchon et al. [15]
52/F
Simultaneous
Hydroxyurea, imatinib
6
Hussein et al. [7].
64/M
Simultaneous
Phlebotomy, imatinib
9
CMR/positive
Hussein et al. [4].
55/M
Simultaneous
Imatinib
23
CMR/positive
Pastore et al. [16]
42/F
Simultaneous
Imatinib, dasatinib
96
MMR/positive
Pardini et al. [8]
67/M
Simultaneous
Imatinib
9
MMR/positive
Gattenlohner et al. [17]
67/M
Simultaneous
Imatinib
14
CMR/positive
Inokuchi et al. [11].
43/M
Simultaneous
Interferon-alpha, hydroxyurea, imatinib, dasatinib
156
CMR/negative
Ursuleac et al. [18]
61/M
84 (CML after MPN)
Hydroxyurea, Imatinib
24
CMR/positive
Hussein et al. [7].
32/M
40 (CML after MPN)
Anagrelide, hydroxyurea, imatinib
9
MMR/positive
Pingali et al. [19]
39/M
241 (CML after MPN)
Phlebotomy, imatinib, dasatinib, nilotinib
41
CMR/positive
Lee et al. [20]
53/M
118 (MPN after CML)
Interferon-alpha, imatinib, anagrelide, hydroxyurea
100
MMR/positive
Lee et al. [20]
60/F
30 (MPN after CML)
Imatinib, nilotinib, anagrelide
32
MMR/positive
Caocci et al. [10] Present case
70/M 21/F
NA Simultaneous
Interferon-alpha, imatinib Imatinib
6 42
CCyR/positive CMR/positive
CML chronic myeloid leukemia, M male, F female, TKIs Tyrosine kinase inhibitors, CMR complete molecular remission, CCyR complete cytogenetic remission, MMR major molecular response, MPN myeloproliferative neoplasm, NA not available
Interestingly, our patient achieved rapidly molecular remission of CML under the treatment with imatinib. As shown in Table 1, near all the patients treated with tyrosine kinase inhibitor had a good response of BCR-ABL positive clonal population of cells. We speculate that the JAK2V617F mutation have no influence on the clinical course of CML. That is important because in most cases, the clinical phenotype is consistent with CML. It suggests the contribution of BCR-ABL to disease progression is greater than that of JAK2 V617F. However, while imatinib treatment induced cytogenetic CML remission, the JAK2 V617F clone persisted in our patient, a phenomenon observed in most previous cases (Table 1). Of the 4 patients examined during a long-term follow-up, 3 patients developed PMF at a median time of 27 months (range 9–48 months) [4, 5, 8], and 1 showed progression to PV after 6 years [6]. In one case, the JAK2 V617F mutation was undetectable after the patient achieved a partial cytogenetic response to imatinib treatment [9]. Notably, in another interesting case, both the BCR-ABL fusion gene and the JAK2V617F mutation were not detectable after dasatinib
therapy [11]. It would be interesting to know if the new generation tyrosine kinase inhibitors or the possibility of combining treatment with tyrosine kinase and JAK2 inhibitors could be more effective for this rare clinical entity of CML. The biological relationships between the two molecular rearrangements BCR-ABL fusion gene and JAK2 V617F mutation in one patient are still unclear. In the present case, during the clinical course, the BCR-ABL decreased with the response of imatinib treatment, but the positivity of JAK2 V617F continued. As most cases presented the BCR-ABL and JAK2V617F mutation, we would speculate that the JAK2V617F and BCR-ABL were present in the two different clones. Recently, Wang et al. [13] reported that that both the JAK2 V617F mutation and BCR-ABL can occur concurrently in both CFU-GM and BFU-E. In summary, we reported a rare CML patient with the coexistence of BCR-ABL and the JAK2 V617F mutation. She had a good response of imatinib therapy. However, further molecular targeted therapeutic strategies have to be developed.
123
90 Conflict of interest peting interests.
W. Xu et al. The authors declare that they have no com-
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