Abstract 2846: Investigation of mechanisms that result in health disparity for Hispanic/Latino patients with B acute lymphoblastic leukemia
Authors: Schramm Joseph W. , He Bing , Ding Yali , Singh Chingakham , Bogush Daniel , Dovat Katarina , Tukaramrao Diwakar Bastihalli , Bhalodia Riya , Dovat Sinisa 
Published: March 2024

Abstract
Although social determinants of health have a large impact on health disparity, biologic vulnerabilities - particularly in cancers that impact at-risk populations are important. Amongst children with Acute Lymphoblastic Leukemia (ALL), the Hispanic/Latino (H/L) population is vulnerable given since the risk of developing ALL is 1.2-1.75 that of Non-Hispanic White children. After corrections for socioeconomic impacts, the mortality for H/L children is 40% higher than NHW. H/L children have a higher rate of high-risk genetic variations: 2-fold rate of heterozygous IKZF1 deletion (IKZF1-del) and a 4-fold rate of CRLF2 translocation. IKZF1 deletion and CRLF2 translocations are associated increased risk of relapse and chemotherapy resistance in B ALL. IKZF1 is an important transcriptional factor and epigenetic regulator that affects global gene transcription in hematopoietic cells. Simultaneous IKZF1-del and CRLF2 translocation represented 94% of H/L children with CRLF2 translocation. Although only 49% of all H/L patients with IKZF1-del had a CRLF2 translocation. Transcriptomics were analyzed for 42 H/L and 18 NHW patient samples using RNAseq. Gene expression from H/L patients was compared to expression in NHW patients and differentially expressed genes were analyzed. Gene set enrichment analysis (GSEA) revealed downregulation of processes responsible for genome maintenance including DNA replication, DNA templated transcription elongation, double strand break repair, and recombinational repair. Ingenuity pathway analysis (IPA) revealed upregulated pathways in stress related translation, histone deacetylases, interferon, and FLT3 signaling compared to NWH. H/L specimens resulted in decreased expression for FGF pathways, ceramide, and FAK signaling. We performed the same analysis in H/L and NHW with wildtype IKZF1 to compare these two population without high risk structural variants. GSEA analysis showed downregulated Intra S DNA Damage checkpoint signaling, DNA replication checkpoint signaling, glutamine amino acid synthesis, and aspartate amino acid synthesis. IPA showed upregulated interferon, histone deacetylases, TREM1 signaling, and Tec Kinase signaling. IPA showed downregulated Ephrin and CDK5 signaling. DNA methylation patterns were compared between 8 H/L and 8 NWH B ALL samples which showed differential methylation patterns affecting multiple cancer relevant genes.In conclusion, these data represent biologic vulnerability in H/L patients with B ALL in comparison to NWH regardless of high-risk genetic variants. H/L B-ALL shows deregulated maintenance of the genome via replication and repair pathways as well as potential vulnerabilities related to regulation of glutamate/aspartate synthesis. These findings give insight into potential mechanisms that can explain increased frequency of high-risk genetic variants in H/L B ALL.
Citation Format: Joseph W. Schramm, Bing He, Yali Ding, Chingakham Singh, Daniel Bogush, Katarina Dovat, Diwakar Bastihalli Tukaramrao, Riya Bhalodia, Sinisa Dovat. Investigation of mechanisms that result in health disparity for Hispanic/Latino patients with B acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2846.