The paradox of myeloid leukemia of Down syndrome

Wayne State University, Detroit MI

Investigators

Abstract

Project Summary Acute myeloid leukemia (AML) and myelodysplasia in children with Down syndrome (DS) are known collectively as myeloid leukemia associated with DS (ML-DS). ML-DS patients have high event-free survival (EFS) rates (89.9%) treated exclusively with cytarabine (AraC)-based protocols. In contrast, ML-DS patients with relapsed disease have extremely poor clinical outcomes with OS rates of <35%, despite salvage therapies including stem cell transplants, highlighting the need to improve our understanding of ML-DS biology and develop novel therapies for patients with relapsed disease. Our studies have identified that ML-DS blasts are significantly more sensitive to AraC compared to AML blasts from children without DS. Further, increased expression of chromosome 21-localized gene cystathionine-ß-synthase (CBS) is linked to the enhanced AraC sensitivities. Metabolomic profiling of ML-DS cell lines revealed reduced levels of cystathionine and cysteine in the AraC- resistant lines compared to the AraC-sensitive ML-DS cell line, indicating reduced CBS activity and suggesting that decreased CBS activity plays an important role in AraC resistance in ML-DS. Other metabolic changes secondary to CBS overexpression contribute to the DS phenotype including elevated levels of H2S, which inhibits mitochondrial Complex IV activity, induces mitochondrial dysfunction, and decreases oxidative phosphorylation (OXPHOS). It has been reported that non-DS AML cells with acquired AraC resistance have increased OXPHOS and targeting OXPHOS could overcome resistance to AraC. Hence, we hypothesize that another mechanism accounting for the enhanced AraC sensitivity of ML-DS blasts relates to mitochondrial dysfunction and decreased OXPHOS due to CBS overexpression. On the other hand, refractory/relapsed (R/R) ML-DS have increased OXPHOS due to decreased CBS activity, leading to resistance to AraC. Moreover, expression of the anti- apoptotic proteins Bcl-2 and Mcl-1 also contribute to AraC resistance. Thus, co-targeting of OXPHOS, Mcl-1, and Bcl-2 may represent a promising approach to treat R/R ML-DS. Our studies of the novel imipridone ONC213, revealed that ONC213 potently suppresses OXPHOS in non-DS AML and downregulates Mcl-1 in both non-DS AML and ML-DS, and synergistically enhances the antileukemic activity of the Bcl-2 selective inhibitor, venetoclax, in both non-DS AML and ML-DS cells. Hence, the combination of ONC213 and venetoclax may effectively eradicate AraC-resistant ML-DS cells. Our proposed studies will 1) determine the role of CBS in OXPHOS and AraC sensitivity/resistance in ML-DS cells and 2) use ONC213 in combination with venetoclax as an approach to target AraC-resistant R/R ML-DS cells. Studying the relationship between CBS overexpression and AraC sensitivity will improve our understanding of ML-DS biology, which may also lead to development of new treatments for non-DS AML patients. Developing new treatments for R/R ML-DS, may improve outcomes for this very therapy-resistant subgroup of patients.