Abstract A11: A pediatric ETV6-ABL1-positive acute lymphoblastic leukemia case with ETV6-ABL1-independent resistance to tyrosine kinase inhibitor
Authors: Uemura Suguru , Hasegawa Daiichiro , Shono Akemi , Thwin Khin Kyae Mon , Nino Nanako , Takafuji Satoru , Mori Takeshi , Tamura Akihiro , Yamamoto Nobuyuki , Saito Atsuro , Kishimoto Kenji , Ishida Toshiaki , Kosaka Yoshiyuki , Iijima Kazumoto , Nishimura Noriyuki 
Published: February 2019

Abstract
Introduction: ETV6-ABL1 fusion represents a rare subgroup of pediatric acute lymphoblastic leukemia (ALL) with unfavorable outcomes. ETV6-ABL1-positive ALL is recently identified in Philadelphia chromosome (Ph)-like ALL and exhibits a gene expression profile similar to BCR-ABL1-positive ALL. Analogous to BCR-ABL1 fusion, ETV6-ABL1 fusion results in the formation of constitutively active non-receptor tyrosine kinases that can also be targeted by selective ATP-competitive tyrosine kinase inhibitors (TKIs). Since TKIs are currently incorporated into the standard treatment of BCR-ABL1-positive ALL, they will be a promising option also for the treatment ETV6-ABL1-positive ALL. However, TKI resistance becomes a common problem in TKI-treated patients, where it is frequently caused by BCR-ABL1-dependent alterations including mutations, genomic amplification, and enhanced expression of BCR-ABL1-fusion kinase. In addition, BCR-ABL1-independent alterations have also been reported to cause TKI resistance. It includes a variety of activating and/or inactivating alterations in RAS, NF-kB, PI3K-AKT, and JAK-STAT signaling pathways that mediate the oncogenic activity of BCR-ABL1 fusion kinase. In contrast, the molecular mechanisms of TKI resistance have been poorly described in ETV6-ABL1-positive ALL, except for T315I mutation of ETV6-ABL1 fusion gene in a single patient and K89M mutation of GNB1 gene in a cell line model.
Patient and Results: A previously healthy 14-year-old girl was admitted to our hospital because of persistent fever. Laboratory data showed white blood cell count of 417,800 /µL and increased LDH level and uric acid level. Bone marrow examination showed nuclear cell count of 855,000 /µL with 90.0% blastic cells of lymphoid morphology. Bone marrow blasts at initial diagnosis were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c; had a karyotype of 45, XX, -7; and were sensitive to TKIs (imatinib and dasatinib) in vitro. A split signal analyzed by ABL1 FISH probe was positive (92.7%), while major and minor BCR-ABL1 fusion transcripts were not detected by RT-qPCR. She was treated with the high-risk protocol based on BFM 95 protocol because of prednisolone poor response. After induction chemotherapy, she achieved complete remission (CR) without ABL1 split signal and IgH gene rearrangement. However, she relapsed 19 months after initial diagnosis, and failed to achieve second CR by alternating administration of dasatinib and antileukemic drugs. Bone marrow blasts at initial diagnosis and after relapse were subjected to whole-transcriptome sequencing. ETV6-ABL1 fusion transcripts were identified in both initial diagnostic and relapsed samples, and their level of expression was not significantly changed. No known alteration in ETV6-ABL1 fusion and GNB1 genes was detected. These results suggested a novel mechanism of TKI resistance in ETV6-ABL1-positive ALL.
Conclusion: To our knowledge, this is a first case of ETV6-ABL1-positive ALL who acquired ETV6-ABL1-independent TKI resistance. It will provide a foundation for the treatment of TKI-resistant ETV6-ABL1-positive ALL.
Citation Format: Suguru Uemura, Daiichiro Hasegawa, Akemi Shono, Khin Kyae Mon Thwin, Nanako Nino, Satoru Takafuji, Takeshi Mori, Akihiro Tamura, Nobuyuki Yamamoto, Atsuro Saito, Kenji Kishimoto, Toshiaki Ishida, Yoshiyuki Kosaka, Kazumoto Iijima, Noriyuki Nishimura. A pediatric ETV6-ABL1-positive acute lymphoblastic leukemia case with ETV6-ABL1-independent resistance to tyrosine kinase inhibitor [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A11.