CCDC88C‐FLT3 gene fusion in CD34‐positive haematopoietic stem and multilineage cells in myeloid/lymphoid neoplasm with eosinophilia

To the Editor, Rearrangements of PDGFRA, PDGFRB, FGFR1 or JAK2 are established features of myeloid/lymphoid neoplasms with eosinophilia (MLNEo).1 The rearrangement of the fmsrelated tyrosine kinase 3 (FLT3) gene should also be associated with MLNEo, and ETV6, SPTBN1, GOLGB1 and TRIP11 have been identified as FLT3 rearrangement partner genes2 (Figure S1). Cases of MLNEo with FLT3 rearrangement are rare but have a poor outcome. We encountered a patient who achieved a favourable longterm outcome by allogeneic haematopoietic stem cell transplantation (alloHSCT) and without using tyrosine kinase inhibitors, despite being refractory to conventional chemotherapy. The coiledcoil domain containing an 88C (CCDC88C)FLT3 translocation was identified in this patient who was diagnosed with myeloid neoplasm with Tcell lymphoblastic lymphoma (TLBL). Chronic myelomonocytic leukaemia (CMML) was one of the differential diagnoses for the current patient; the criteria of chronic myelomonocytic leukaemia included not having the specific genes, such as PDGFRA, if eosinophilia was present.1 The current case showed a FLT3 rearrangement, and therefore we considered a diagnosis of MLNEo as reasonable. The CCDC88CFLT3 translocation was identified in TLBL, CD34positive haematopoietic stem and multilineage cells.


CCDC88C-FLT3 gene fusion in CD34-positive haematopoietic stem and multilineage cells in myeloid/lymphoid neoplasm with eosinophilia
To the Editor, Rearrangements of PDGFRA, PDGFRB, FGFR1 or JAK2 are established features of myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo). 1 The rearrangement of the fms-related tyrosine kinase 3 (FLT3) gene should also be associated with MLN-Eo, and ETV6, SPTBN1, GOLGB1 and TRIP11 have been identified as FLT3 rearrangement partner genes 2 ( Figure S1). Cases of MLN-Eo with FLT3 rearrangement are rare but have a poor outcome.
We encountered a patient who achieved a favourable long-term outcome by allogeneic haematopoietic stem cell transplantation (allo-HSCT) and without using tyrosine kinase inhibitors, despite being refractory to conventional chemotherapy. The coiled-coil domain containing an 88C (CCDC88C)-FLT3 translocation was identified in this patient who was diagnosed with myeloid neoplasm with T-cell lymphoblastic lymphoma (T-LBL). Chronic myelomonocytic leukaemia (CMML) was one of the differential diagnoses for the current patient; the criteria of chronic myelomonocytic leukaemia included not having the specific genes, such as PDGFRA, if eosinophilia was present. 1 The current case showed a FLT3 rearrangement, and therefore we considered a diagnosis of MLN-Eo as reasonable. The CCDC88C-FLT3 translocation was identified in T-LBL, CD34-positive haematopoietic stem and multilineage cells.

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A 50-year-old woman was admitted to our hospital. Her bone marrow aspiration showed hypercellular marrow (>90% cellularity) with increased myeloid cell numbers and abundant eosinophils (10%-20% all nucleated bone marrow cells ( Figure S2A)). In addition, T-LBL was detected in a tonsil biopsy. Tonsil biopsy showed areas with abnormal proliferating lymphoblasts and immunohistochemical findings revealed that abnormal lymphocytes were positive for CD3, CD5, CD7, CD4, CD8, CD56, TdT, CD99 and bcl-2. The CD4/CD8 ratio was high. Since eosinophils in tonsil specimen were not so condense as in bone marrow, the presence of MLN-Eo cells were unclear. JAK2 Assuming that allo-HSCT would be necessary, conventional chemotherapy was started. The first line regimen was an intensive acute lymphoblastic leukaemia protocol. 3 The patient's clinical course is shown in Figure S2D. The disease was strongly refractory to conventional chemotherapy. We therefore biopsied the right groin lymph node when it regrew after second-line chemotherapy (Hyper-CVAD) and detected not only T-LBL cells but also MLN-Eo cells ( Figure S2A). narrow areas on exon 13, 14 and 15 between the TK domain and juxtamembrane area ( Figure S1). Therefore, we investigated the breakpoint using inverse RT-PCR (Table S1). We first identified the breakpoint using cDNA ( Figure 1A,B) and then determined the precise breakpoint using DNA ( Figure 1B). Sequencing of the junction using cDNA revealed that one nucleotide was deleted ( Figure S1B) through splicing from RNA to cDNA. We specified the CCDC88C gene on chromosome 14 and the precise breakpoint. Band q12 on chromosome 13 was thus identified as corresponding to FLT3 and band q32 on chromosome 14 was identified as CCDC88C. While one study reported that CCDC88C was a fusion partner gene to PDGFRB, 4 CCDC88C-FLT3 has only previously been reported in one case of juvenile myelomonocytic leukaemia in a 20-week-old boy. 5 Therefore, this is the first case of MLN-Eo with CCDC88C-FLT3 translocation.
The CCDC88C breakpoint in the current case and previous report 5 were located in the intron after exon 22 and intron after exon 23 respectively. The FLT3 breakpoint was located in exon 14. The  Table S1). The nested RT-PCR results for each single cell are shown in Figure 1C. This study was performed in accordance with the Declaration of Helsinki, and informed consent was obtained from the patient for publication of this report.

CO N FLI C TO FI NTE R E S T
The authors declare no competing financial interests.

DATAAVA I L A B I L I T YS TAT E M E N T
The data that supports the findings of this study are available in the supplementary material of this article.