Abstract 2053: Structural variants detected by optical genome mapping in acute lymphoblastic leukemia patient-derived xenografts models
Authors: Wang Yueying , Qin Mengting , Liu JinPing , Chen Xiaobo , Xue Jia , Guo Sheng 
Published: April 2023

Abstract
Background: The established classification of acute lymphoblastic leukemia (ALL) does not cover all high-risk patients because of the difficulty in detecting novel or rare structural variants (SVs). Furthermore, many SVs and formed gene fusions have adverse prognostic effects on hematological malignancies. This study aims to investigate SVs in 22 patient-derived xenografts (PDX) of ALL and to assess rare SVs and chromosomal aberrations, particularly hematological malignancy genes and gene fusions in different individuals detected by optical genome mapping (OGM).
Methods: Leukemia cells from 16 patients with B-cell precursor acute lymphoblastic leukemia (B-ALL) and 6 patients with T-cell acute lymphoblastic leukemia (T-ALL) were inoculated into immuno-deficient mice, growth curves were monitored, and leukemia cells were collected after human CD45 was more than 80%. OGM (Bionano Genomics), RNA sequencing (RNA-seq) and whole genome sequencing (WGS) techniques were used to detect SVs and gene fusions. In validation, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) tests were performed to identify specific SVs.
Results: On average, each model detected 42 rare SVs with known overlapping genes in different types by OGM: 12 insertions, 25 deletions, 1 inversion, 3 duplications, 2 inter-chromosomal translocations and 1 intra-chromosomal translocation. 5 rare SVs were found in multiple models (&gt;=5), and two of them were never reported in B-ALL and T-ALL. Gene fusions were detected in all ALL models by OGM, and 17% were novel fusions. At the mRNA level, gene fusions were detected only in 19 models, and 24% of the predicted gene fusions by OGM were identical to the results of RNA-seq (high confidence results including pseudogenes). These two technologies could detect different fusion partners. For example, MLLT1 was seen at the mRNA level, and ACER1 was detected at the DNA level in the same KMT2A rearrangement model. Of the 16 B-ALL models, 6 were p190 BCR-ABL1 (a fusion of BCR exon 1 and ABL1 exon 2), 1 was p210 BCR-ABL1 (a fusion of BCR exon 13 and ABL1 exon 2) and 5 of 7 had IKZF1 gene deletions. 2 p190 BCR-ABL1 models were insensitive to imatinib and 2 p190 BCR-ABL1 models as well as the model with IKZF1 exons 4-7 deletion were sensitive to imatinib when treatment was initiated early in the disease. A novel ARL15-IKZF1 fusion was identified in one of the sensitive models. Deletion of the PRKAR2B gene was another rare SV in both models sensitive to imatinib besides the IKZF1 deletion.
Conclusion: OGM assays were more comprehensive, and novel rare SVs were identified in ALL. Combining the results of gene fusions between different technologies will provide more accurate predictions for ALL classifications. The combination of aberrant SVs may synergize to influence the efficacy of imatinib, which warrants further investigations.
Citation Format: Yueying Wang, Mengting Qin, JinPing Liu, Xiaobo Chen, Jia Xue, Sheng Guo. Structural variants detected by optical genome mapping in acute lymphoblastic leukemia patient-derived xenografts models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2053.