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2981 A Novel Transgenic Mouse Model of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities

Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Non-Biological therapies, Diseases, Therapies, Lymphoid Malignancies, Pharmacology, Biological Processes, molecular biology
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Jacob J. Junco, PhD1*, Raushan Rashid1*, Maci Terrell1*, Michelle Alozie1*, Max Rochette1*, Barry Zorman, PhD1*, Pavel Sumazin, PhD1*, Lauren Rowland2*, Gino Dettorre2*, Reid T. Powell, PhD3*, Clifford C. Stephan, PhD3*, Peter J. Davies, MD, PhD3*, Margie M. Moczygemba, PhD3*, Jun J. J. Yang, PhD4 and Karen R. Rabin, MD, PhD5

1Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX
2Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
3Institute of Biosciences and Technology, Texas A&M University, Center for Translational Cancer Research, Houston, TX
4Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, MEMPHIS, TN
5Department of Pediatrics, Baylor College of Medicine, Baylor College of Medicine TX Children's Cancer Center, Houston, TX

Background: Children with Down syndrome (DS) have a 10-fold increased risk of developing B-cell acute lymphoblastic leukemia (B-ALL), and they have poorer survival due to increased relapses and treatment-related mortality (TRM). Targeted therapies for DS-ALL are needed to improve anti-leukemic efficacy and reduce the risk of TRM. Mouse models and cell lines recapitulating DS-ALL are lacking, and may aid in identifying new targets for DS-ALL.

Methods: We used the Dp(16)1Yey (Dp16) mouse model of DS, which has a triplication of ~115 human chromosome 21 (Hsa21) orthologues. We introduced KrasG12D and Pax5 heterozygosity, both driven in B cells by CD19-Cre, in Dp16 and non-DS wild-type (WT) mice. We performed RNA-Sequencing (RNA-Seq) and gene set enrichment analysis (GSEA) to identify differentially regulated signaling pathways in Dp16 and WT B-ALL blasts. We cultured B-ALL blasts from mice to generate immortal cell lines. We tested the chemosensitivity of Dp16 and WT B-ALL cell lines with 35 agents with known efficacy in hematologic malignancies, and with 481 anti-cancer compounds used in the Cancer Therapeutics Response Portal project, to screen for drugs effective in DS-ALL. We screened top candidate drugs in DS-ALL and non-DS ALL patient samples in vitro, and tested FK866 and cucurbitacin I in vivo in mice xenografted with a DS-ALL patient sample.

Results: KrasG12D.Pax5+/- mice developed B-ALL with complete penetrance, with significantly shorter median survival in the Dp16 versus WT background (Figure 1A; 80 versus 114 days, p<0.0001). GSEA demonstrated upregulation of DNA repair signaling pathways in Dp16 B-ALL, recapitulating a signature observed in human DS-ALL. Growth of Dp16 and WT B-ALL cell lines, and DS-ALL and non-DS ALL patient samples, was inhibited at low nanomolar concentrations by novel therapies targeting NAMPT, DNA damage responses, autophagy, and JAK and PI3K/mTOR signaling. In mice xenografted with a DS-ALL patient sample, the NAMPT inhibitor FK866 significantly reduced the leukemic burden compared to vehicle (Figure 1B; 14.6% vs 22.4% after 4 weeks of treatment, p<0.005). The effect of FK866 was also significant after weeks 2 and 3 of treatment.

Conclusions: We have generated the first de novo mouse model and cell lines recapitulating DS-ALL, which we have employed in drug screens to identify novel therapeutic approaches. These studies suggest promising candidates for further study in DS-ALL and other high-risk ALL subtypes to reduce toxicity and improve outcomes.

Disclosures: Yang: Takeda Pharmaceutical Company: Research Funding; AstraZeneca plc: Research Funding.

*signifies non-member of ASH