Marie-France Gagnon received her MD at the University of Montreal. Subsequently, she completed her Medicine residency and Hematology fellowship at the University of Montreal. She also holds a master’s degree in biomedical sciences focusing on the genetic determinants of hematopoiesis from this institution. She is currently training as a fellow in Laboratory Genetics and Genomics at Mayo Clinic.
Marie-France Gagnona, James Smadbecka, Neeraj Sharmaa, Patrick Blackburnb, Jonna Demasi Benevidesa, Yassmine Akkaric, Jennifer Jaroscakd, Iya Znoykod, Daynna Wolffd, Cynthia Schandld, Reid Meyera, Patricia Greippa, Xinjie Xua, Nicole Hoppmana, Rhett Ketterlinga, Jess Petersona, Linda Baughna
aMayo Clinic, Rochester, MN, USA; bSt. Jude Children’s Research Hospital, Memphis, TN, USA; cLegacy Health, Portland, OR, USA; dMedical University of South Carolina, Charleston, SC, USA
Primary cytogenetic abnormalities in B-lymphoblastic leukemia (B-ALL) define subgroups of disease with distinct clinical implications. These subgroups are largely mutually exclusive and only rarely observed in conjunction. We describe a three-year-old female presenting with de novo B-ALL in whom dual color, dual fusion fluorescence in situ hybridization (D-FISH) evaluation suggested concurrent ETV6::RUNX1 and KMT2A::MLLT3 rearrangements. Chromosomal microarray analysis (CMA) indicated that the breakpoint within KMT2A was located outside the typical region described in KMT2A leukemogenic translocations. Owing to the unexpected identification of concurrent ETV6::RUNX1 and KMT2A translocations by D-FISH and the suspicious findings on CMA, research-based whole genome sequencing (WGS) was performed. While this analysis confirmed the ETV6::RUNX1 fusion, WGS revealed the apparent KMT2A::MLLT3 fusion detected by D-FISH resulted from a juxtaposition of the 3′ portion of KMT2A (from intron 1) to an intergenic region on chromosome 9 located 460 Kb upstream of MLLT3. The WGS results indicate the apparent KMT2A::MLLT3 rearrangement would not result in an oncogenic chimeric fusion protein, and the characteristic KMT2A::MLLT3 dual fusion identified by D-FISH testing represented a false-positive FISH result. WGS thus more precisely resolved the genomic abnormalities in this B-ALL clone in comparison to chromosomes, FISH and chromosomal microarray and enabled accurate risk stratification. This case illustrates the importance of careful interpretation of atypical cases with aberrant genomic results, comprehensively considering expected fusion product structure, assay design and integrating results in their entirety. WGS may provide a means for resolution of atypical results by standard investigation modalities.