SSRP Abstract

Board 16: Investigating the Oncogenic Potential of Mutations Common in Down Syndrome Acute Lymphoblastic Leukemia (DS-ALL)

Student Scientist: Ali Amer ’23
Research Mentor: Jacob J. Junco (Rabin Lab, Department of Pediatrics, Texas Children’s Cancer Center)

Children with Down syndrome (DS) have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and are associated with poorer outcomes than children without DS. Furthermore, DS-ALL features a unique spectrum & frequency of mutations compared to non-DS-ALL. Our study aimed to determine the oncogenic potential of CEBPD (a genetic alteration more common in DS-ALL) overexpression and other common co-occurring mutations in DS-ALL.

Patients with Down syndrome (DS) have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL) and have a poorer prognosis than children without DS. Furthermore, DS-ALL features a different spectrum of mutations compared to non-DS ALL. Our goal was to determine if overexpression of CEBPD, an alteration more common in DS-ALL, demonstrates greater oncogenic effects in the DS genetic background, which would provide functional data supporting the increased frequency of this alteration that is observed in DS-ALL. To test this, we overexpressed CEBPD via lentiviral transduction in hematopoietic stem cells from the Dp16 mouse model of DS and wild-type (WT) non-DS control mice. Next, we compared the growth of flow cytometry-sorted transduced cells in a B-cell methylcellulose colony serial replating assay to determine the oncogenic potential of tested mutations in a DS and non-DS background. CEBPD induced a significant (p<0.05) increase in B-cell colonies in the Dp16 background compared to the WT background. This effect was observed with the initial plating, but not on subsequent replating. For all conditions tested, colony counts decreased over four serial replatings, indicating that CEBPD overexpression alone was not sufficient to transform the cells. We also tested the effects of other alterations observed more frequently in DS-ALL, Kras^G12D and Flt3. We observed no effect of Kras^G12D on colony growth, and effects of Flt3 mutations are pending. These results provide functional evidence of some enhanced B cell proliferation driven by CEBPD in the DS genetic background, which may contribute to the increased prevalence of CEBPD-overexpressing alterations in DS-ALL.