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Letters to the Editor
to acute leukemia (3 AML, 2 B-ALL, and 1 T-ALL) and all died shortly after transformation despite the addition of TKI to the standard chemotherapy.3-8 In contrast, four other MPN patients (with no increased blasts) who received TKI achieved long-term survival (longest sur- vival 9 years),1,2,11 similar to the experience at our institu- tion. Therefore, it appears to be of paramount impor- tance to identify this fusion and incorporate TKI treat- ment at an early stage of disease. High index of suspicion is critical to initiate proper testing in patients presenting with signs of MPN and eosinophilia. With disease pro- gression, TKI response may be limited. Considering the clinicopathologic similarities (myeloid proliferation, eosinophilia, basophilia, and transformation to AML, B-ALL and T-ALL) between these cases and sensitivity to TKI treatment, we propose classifying them as one group: myeloid/lymphoid neoplasms with eosinophilia/basophilia and ETV6-ABL1 fusion. Our find- ings do not favor a diagnosis of Ph- CML or atypical CML based on the pathologic features, eosinophilia and poten- tial transformation to T-ALL.
Due to the cryptic nature of t(9;12), the incidence of ETV6-ABL1 fusion might have been underestimated in the literature. The presence of additional ABL1 signal by FISH studies in the absence of BCR-ABL1 fusion is a clue to search for other ABL1 fusions in a subset of cases. FISH analysis using ETV6 and ABL1 break-apart probes and RNA-based NGS assay are able to detect the fusion with high sensitivity. RNAseq NGS assay has recently been developed for fusion detection in hematologic malignan- cies, which can overcome the technical barriers in the identification of ETV6-ABL1 fusion by traditional meth- ods. Our laboratory’s panel has extensive ETV6 and ABL1 coverage, facilitating the detection of both ETV6-ABL1 and any other novel ETV6 or ABL1 fusions. With the wide application of RNAseq assay, we expect that more fusions will be detected in hematologic malignancies. RNAseq assay can also elucidate transcript type, critical in determining “A versus B”.16 Type A involves ETV6 exon 4, whereas type B involves exon 5, joining to ABL1 exon 2; type B is the prevalent transcript form (17 of 18 cases in Online Supplementary Table S3), detected in five patients with ETV6-ABL1 fusions in our institution. As a member of Ets family of transcription factors, when ETV6 fuses to a receptor tyrosine kinase, the fusion pro- tein displays an elevated tyrosine kinase activity. Type B has higher kinase activity since ETV6 exon 5 includes a direct binding site for the SH2 domain of the GRB2, which enhances the PI3-kinase and MAP Kinase path- ways.17 Consistently, ERK phosphorylation was increased in ETV6-ABL1 positive marrow cells. In addition, STAT5 phosphorylation was also upregulated similar to observa- tions in BCR-ABL1 CML, although this needs to be con- firmed in more patients.
In summary, our approach combining flow cytometry sorting technology and downstream FISH studies clearly demonstrated ETV6-ABL1 fusions in sorted HSC, myeloid progenitors/blasts, granulocytes and monocytes but not lymphocytes, suggesting an HSC origin. The mechanism of this fusion driving myeloid/lymphoid dif- ferentiation remains to be investigated. Patients with these fusions typically present initially as myeloid/lym- phoid proliferation with eosinophilia/basophilia and show hypersensitivity to TKI treatment. Early identifica- tion by FISH (particularly by ETV6 probes) and/or RNA sequencing and potential for such therapy is advanta- geous based on the current and published experience with this rare neoplasm. We propose to classify this group of disease as myeloid/lymphoid neoplasms with
eosinophilia/basophilia and ETV6-ABL1 fusion to facili- tate and unify the clinico-pathologic and molecular diag- nosis and subsequent clinical management. Development of a quantitative polymerase chain reaction assay similar to BCR-ABL1 fusion is needed for future dis- ease and therapy monitoring.
Jinjuan Yao,1,* Lianrong Xu,1,* Umut Aypar,1,*
Howard J. Meyerson,2 Dory Londono,1 Qi Gao,1
Jeeyeon Baik,1 James Dietz,1 Ryma Benayed,1 Allison Sigler,1 Mariko Yabe,1 Ahmet Dogan,1 Maria E. Arcila,1
Mikhail Roshal,1 Yanming Zhang,1 Michael J. Mauro3and Wenbin Xiao1
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Pathology, University Hospitals of Cleveland, Cleveland, OH and 3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
*JY, LX and UA contributed equally as co-first authors.
Correspondence:
WENBIN XIAO - xiaow@mskcc.org
doi:10.3324/haematol.2020.249649
Disclosures: WX has received research support from Stemline Therapeutics. MJM has served as a consultant/advisor for Novartis, Pfizer, Bristol-Myers Squibb, Takeda/Millennium, and receives institu- tional research support from Bristol-Myers Squibb, Novartis, and Sun Pharma/SPARC. The other authors have no conflicts of interest to dis- close.
Contributions: JY, LX, YZ, MJM and WX conceived the study, col- lected and analyzed the data, and wrote the manuscript; UA, DL, and YZ performed cytogenetic studies and interpreted the data; HM con- tributed critical clinical materials; QG, JB, JD, RB, MY, NS and AEM collected data; AD and MR interpreted the data. All the authors approved the final version of the manuscript.
Funding: This study was supported in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.
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