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Chronic phase of ETV6‐ABL1 positive CML responds to imatinib

Imatinib acts as an effective agent for inhibiting the neoplastic clone in patients with BCR-ABL1positive CML by blocking the constitutively activated BCR-ABL1 kinase (Druker, 2003). Rare patients (<5%)withmorphological CMLdo not demonstrate this gene rearrangement (Onida et al., 2002; Druker, 2003). The presence of a novel gene fusion between ETV6 and ABL1 has been reported in patients with BCR-ABL1-negative CML (Andreasson et al., 1997). We report a patient who was diagnosed with BCR-ABL1-negative, ETV6-ABL1-positive chronic phase CML. Treatment with imatinib has produced an excellent hematological response. A 24-years-old female was referred in September, 2007 because of a 3 month history of leukocytosis. At consultation, her peripheral while blood cell (WBC) counts were 98,800/ll (blasts 2%, promeylocytes 6%, myelocyte 17%, metamyelocytes 1%, bands 15%, mature granulocytes 44%, lymphocytes 7%, monocytes 3%, eosinophils 4%, basophils 1%), Hb 11.3 g/ dl, and platelets 261,000/ll. Mild hepato-splenomegaly was detected. Her bone marrow was hyperplastic with normal differentiation. Chromosomal analysis revealed a normal karyotype (data not shown). Neither metaphase fluorescence in situ hybridization (FISH) analysis nor reverse transcription-polymerase chain reaction (RT-PCR) detected evidence of a BCR-ABL1 fusion (Fig. 1A and data not shown). However, the ASS gene, which is centromeric to ABL1, was missing from one copy of chromosome 9 (Fig. 1A). This deletion can be seen in association with the t(9;22) translocation (Sinclair et al., 2000). To explore the genetic abnormalities of this case, we performed single-nucleotide polymorphism genomic microarray (SNP-chip) analysis as previously described (Kawamata et al., 2008) and found duplication of the portion of 12p13 involving the 50 half of ETV6 gene and a deletion of 9q34 involving exon 1 of ABL1 (Fig. 1B). These findings were highly suggestive of a fusion between exons 1-5 of ETV6 and exons 2-11 of ABL1. Metaphase FISH analysis using ETV6, RUNX1, BCR, and ABL1 probes demonstrated a fusion of ETV6 and ABL1 (Fig. 1C) on chromosome 9, suggesting that the duplicated portion of 12q13 was inserted at 9q34.1 (Fig. 1D). RT-PCR analysis of the transcripts using primers specific to the ETV6 and ABL1 genes showed two sizes of PCR products (Fig. 2 A). Nucleotide sequencing of these PCR products demonstrated a fusion between exon 5 of ETV6 and exon 2 of ABL1, as well as a fusion of exon 4 of ETV6 and exon 2 of ABL1 (Fig. 2A). These two fusion products were probably generated by alternative splicing of exon 5 of ETV6. Imatinib treatment (400 mg/day) was started and the patient’s WBC decreased to normal range (7,800/ll) within 5 days (Fig. 2B). Treatment is continuing and the WBC has remained in the normal range for over 7 months (Fig. 2B). At three months after the treatment started, the abnormal cells were not detected by FISH in the peripheral blood (Fig. 2B and data not shown). Previously, a patient with myeloid blastic crisis of ETV6-ABL1-positive CML, who was treated with imatinib, but only responded for only 10 days has been described (O’Brien et al., 2002). Another report described an ETV6-ABL1-positive CML patient with blastic crisis who was placed in a second chronic phase using chemotherapy followed by maintenance treatment with imatinib (Barbouti et al., 2003). The patient remained in second chronic phase for 125 days, when second blastic crisis occurred (Barbouti et al., 2003). Our patient differed from these two cases by having imatinib treatment initiated during chronic phase CML with ETV6-ABL1 and receiving no chemotherapy prior to imatinib treatment, with an excellent response for over 7 months. This is the first report that ETV6-ABL1-positive chronic phase CML can be successfully treated with imatinib.