Clinical significance of myeloproliferative neoplasms with JAK2V617F mutations and major BCR-ABL1 translocations: a literature review with case presentation.

TO THE EDITOR: It is well known that BCR-ABL1 translocations and JAK2V617F mutations are mutually exclusive events in myeloproliferative neoplasms (MPN) [1]. However, the coexistence of both abnormalities has been reported in several cases [123456]. Until now, two studies have reported the co-occurrence of BCR-ABL1 translocation and JAK2V617F mutation in Korea [34]. Here, we discuss the clinical significance through a literature review, especially focusing on cases reported in Korea with a case presentation.

A 68-year-old woman was admitted with increased hemoglobin (Hb) and leukocyte count. Complete blood count (CBC) at admission showed the following: white blood cells, 17.06×109/L; Hb, 17.3 g/dL; and platelets, 245×109/L. Peripheral blood smear demonstrated leukoerythroblastosis with the presence of few tear drop cells. Differential counts of leukocytes were as follows: myelocytes 1%, metamyelocytes 1%, neutrophil 84%, lymphocytes 9%, monocytes 4%, eosinophil 1%, and rare nucleated red blood cells. Her serum lactate dehydrogenase level was elevated (313 IU/L, reference range, 0–250 IU/L) while her serum erythropoietin level was decreased (3.06 mIU/L, reference range, 3.7–37.5 mIU/L). An abdominopelvic computed tomography showed splenomegaly. We could not acquire sufficient information from the bone marrow aspirate, because it was diluted. However, bone marrow biopsy revealed hypercellularity and a slightly increased number of megakaryocytes (3.4/high power field) with dense clustering and certain degree of atypia (Fig. 1). Diffuse myelofibrosis, with bone marrow fibrosis (MF) grade 2, was detected (Fig. 1). Reverse-transcriptase PCR (RT-PCR) assay for the BCR-ABL1 fusion transcript showed the presence of a major BCR-ABL1 fusion transcript (b13a2 type), which was confirmed by sequencing (Fig. 1). The fusion transcript level was 1.23% on the international scale (IS). An allele-specific PCR assay for the JAK2V617F mutation was positive for a heterozygous type JAK2V617F mutation with an allelic burden of 79.20%, which was confirmed by sequencing (Fig. 1). The chromosomal analysis revealed 46,XX karyotype[20]. Interphase fluorescent in situ hybridization for BCR-ABL1 translocation was nuc ish (ABL1, BCR)×2 (ABL1 con BCR×1) [13/500], representing a normal result (below the cutoff level). The final diagnosis revealed MPN, with concurrent JAK2V617F mutation and major BCR-ABL1 translocation. The patient was only treated with hydroxyurea (500 mg, twice a day). After 10 months of treatment, her CBC became normal (5.35×109/L white blood cells, a Hb of 14.9 g/dL, and 185×109/L platelets) and BCR-ABL1 transcripts level was 0.016% IS.

Fig. 1

Bone marrow biopsy showing (A) hypercellular marrow with increased megakaryocytes and atypia (H&E stain, ×400) and (B) myelofibrosis grade MF-2 demonstrated by reticulin staining (reticulin stain, ×200). Reverse transcriptase (RT)-PCR analysis of BCR-ABL1 translocation using a HemaVision kit showing a single 397 bp band in the M6B split out PCR, indicating a fusion transcript with BCR-ABL1 (C). Sequencing analysis of the RT-PCR product showing breakpoint located at exon 13 in the BCR gene and exon 2 in the ABL gene (D). Sequencing analysis of JAK2V617F showing a heterozygous JAK2V617F mutation (E).

Detecting BCR-ABL1 translocation and JAK2V617F mutation simultaneously at the time of diagnosis is a rare event. Recent studies have reported that about 0.2–0.5% of MPN patients are positive for both BCR-ABL1 and JAK2V617F [67]. It has been suggested that most MPN cases with concurrent BCR-ABL1 and JAK2V617F consist of two unrelated clones [268].

The coexistence of these abnormalities may affect laboratory findings and patient diagnosis. Park et al. [3] reported two cases of MPN, with a relative JAK2V617F dominancy over BCR-ABL1 transcripts. Their laboratory findings resembled essential thrombocythemia (ET) and primary myelofibrosis (PMF). Our patient showed a relative dominancy of JAK2V617F, with the laboratory diagnosis resembling PMF. In contrast, the case reported by Yi and Kim [4] showed relatively high levels of BCR-ABL1 transcripts. Laboratory features of both CML and PMF were detected (Table 1). Soderquist et al. [8] have reported that coexistence cases show mixed megakaryocytes characteristics that include both dwarf megakaryocytes, seen in CML, and bulbous megakaryocytes, seen in PMF. Therefore, it is essential to perform tests for BCR-ABL1 and JAK2V617F simultaneously with quantitation, in order to avoid misinterpretation and obtain an accurate diagnosis of MPN.

Table 1

Clinical and hematologic features in Korean MPN patients with concurrent BCR-ABL1 translocation and JAK2V617F mutation.

Abbreviations: CML, chronic myeloid leukemia; ET, essential thrombocythemia; FISH, fluorescence in situ hybridization; IS, international scale; MPN, myeloproliferative neoplasms; NCN, normalized copy number; PCR, polymerase chain reaction.

The molecular abnormality profile can influence the choice of treatment modalities. Cases reported by Park et al. [3] and our patient showed acceptable responses to hydroxyurea. However, the case reported by Yi and Kim [4] showed treatment responses to dasatinib (a tyrosine kinase inhibitor), hydroxyurea, and ruxolitinib (a JAK1/2 tyrosine kinase inhibitor) (Table 1). Other studies [69] have reported successful responses to the simultaneous use of tyrosine kinase inhibitors and hydroxyurea or ruxolitinib in patients with concomitant BCR-ABL1 and JAK2V617F. Therefore, detection of molecular abnormalities is important for appropriate treatment, especially when a decision must be made in the event of therapeutic failure and drug replacement.

Another issue is the impact of molecular abnormalities on patient outcomes. Soderquist et al. [8] have reported that seven of 11 MPN patients with concurrent BCR-ABL1 and JAK2V617F showed progression to myelofibrosis, suggesting that these patients are more prone to disease progression. The coexistence of two molecular abnormalities might accelerate the progression. Nevertheless, cases reported in Korea have shown successful responses without death, at the time of publication [34]. However, data concerning the progression rate and survival of patients with concomitant BCR-ABL1 and JAK2V617F mutations are currently insufficient.

In summary, it is important to recognize the possibility of the coexistence of a BCR-ABL1 translocation and JAK2V617F mutation in MPN, because they can affect hematologic features and treatment strategy. However, it is unclear if MPNs with concomitant BCR-ABL1 translocations and JAK2V617F mutations reflect a novel clinical entity with distinct features and outcomes. Further investigation with a large cohort is needed.