Gordana Raca
Abstract
Gordana Racaa, Alexandra Kovacha, Andrew Doana, Zhaohui Gub, Zunsong Hub, Dejerianne Ostrowa, Venkata Yellapantulaa, Jianling Jia, Ryan Schmidta, Jaclyn Biegela, Deepa Bhojwania
aChildren’s Hospital Los Angeles, Los Angeles, CA, USA; bCity of Hope, Los Angeles, CA, USA
Newly discovered genetic drivers in B-lymphoblastic leukemia (B-ALL) frequently remain undetected by standard karyotype and FISH analyses. At our institution, comprehensive evaluation by karyotyping, FISH, chromosomal microarray and a custom sequencing panel (OncoKids®), identifies a primary driver in 85% of B-ALL cases. In this study we utilized a novel capture-based transcriptome sequencing (RNA-Seq) method and optical genome mapping (OGM) to detect driver fusions in the remaining 15% of B-ALL subtypes.
OGM and RNASeq were performed on 19 and 53 leukemia cases, respectively, with undefined genetic drivers. Subtype-defining abnormalities were detected by RNAseq in 16/53 cases (30%). Twelve of the 16 demonstrated previously described genetic drivers, while 4 cases showed novel fusions at the time of testing. These included an RBM26::JAK2 fusion identified in a 1-year old with standard risk (SR) B-ALL, a STRBP::JAK2 fusion in a 23-year old with high-risk B-ALL; a PAX5::HIPK3 fusion in a 5-year old with SR B-ALL, and an ETV6::MFN2 fusion in a 2-year old with SR B-ALL. OGM demonstrated that the RBM26::JAK2, PAX5::HIPK3 and ETV6::MFN2 fusions originated from translocations, and the STRBP::JAK2 fusion from an inversion. Expression profiling showed a Philadelphia-like signature in the RBM26::JAK2 and STRBP::JAK2 cases, a PAX5Alt signature in the PAX5::HIPK3 case and an ETV6::RUNX1-like signature in the ETV6::MFN2 case.
This study demonstrates clinical utility and discovery potential of RNAseq and OGM in B-ALL classification. Considering the genetic heterogeneity and high discovery rate of novel drivers, non-targeted genome and transcriptome interrogation may be superior to panel testing for clinical B-ALL evaluation.