-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1869 Novel Germline TRAF3IP3 Mutation in a Dyad with Familial Acute B Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation: Poster II
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Biological Processes, Lymphoid Malignancies, genomics
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Lauren Pommert, MD, MS1, Robert Burns, MD2*, Quinlan Furumo3*, Kirthi Pulakanti4*, Jon Brandt5*, Michael J Burke, MD6,7 and Sridhar Rao, MD, PhD8,9

1Cincinnati Children's Hospital Medical Center, Cincinnati, OH
2Blood Research Institute, Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
3Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
4Blood Research Institute, Versiti, Wauwatosa, WI
5Hospital Sisters Heath System St. Vincent Hospital, Green Bay, WI
6Children's Hospital of Wisconsin, Milwaukee, WI
7Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
8Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, Children's Hospital of Wisconsin, Milwaukee
9Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI

Acute lymphoblastic leukemia (ALL) is the most common single malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing has demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. We identified a father-daughter dyad with childhood B cell acute lymphoblastic leukemia (B-ALL) and obtained their diagnostic bone marrow samples from the Children’s Oncology Group (COG) bank in addition to germline samples via remission marrow (daughter) or buccal swab (father). Whole Exome Sequencing (WES) was performed and compared to a panel of normal to identify large genomic changes and single nucleotide variants. In parallel, RNA-sequencing (RNA-seq) was performed on the diagnostic marrows. We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B cell lymphopoiesis and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. This mutation has not been previously described in ALL, however based on the function of TRAF3IP3 in B cell lymphopoiesis, we conclude this likely represents a mutation predisposing to the development of leukemia. WES revealed this dyad had no shared SNVs that are associated with leukemia in the literature and that they had only a few shared SNVs within the leukemia samples, none of which were identified as clinically significant; which suggests the spectrum of their somatic mutations were distinctly different. Given the lack of concordance in their somatic mutational spectrum, we wondered if the two leukemia samples would exhibit a shared transcriptome, implying convergent leukemogenic pathways were altered within the two specimens since they were both clinically reported as hyperdiploid. In comparing the leukemia gene expression profiles identified by RNA-seq to 216 cases of sporadic B-ALL from the TARGET database (The Therapeutically Applicable Research to Generate Effective Treatments program), we discovered that these two leukemia samples did not cluster together but did cluster with other cases of childhood B-ALL. We suspect that this germline TRAF3IP3 mutation increased this dyad’s susceptibility to leukemia development but that the somatic mutational spectrum drove the leukemia development and dictated its phenotype. This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH