Enhancing treatments for myeloid leukemia associated with Down syndrome

PROJECT SUMMARY Myeloid Leukemia associated with Down syndrome (ML-DS) patients have high 5-year overall survival (OS) rates when treated exclusively with cytarabine (AraC)-based protocols. While many notable factors linked to the high curability of ML-DS have been made, the molecular mechanisms are not entirely understood. The bone marrow

microenvironment plays a role in overall leukemogenesis. We have demonstrated endothelial cells (ECs) modulate non-DS AML growth and chemoresistance. However, their impact on the chemosensitivity of ML-DS cells has yet to be fully understood. We have demonstrated that AML-induced EC activation in the bone marrow

leads to subsequent leukemia cell adherence and chemoresistance, identifying this process as integral in the formation of minimal residual disease (MRD) and subsequent relapse. Interestingly, our pilot data show significantly decreased interactions between ML-DS cells with non-DS ECs compared to non-DS AML.

Furthermore, it is well documented that ECs isolated from different tissues as well as disease states (normal vs leukemia) represent heterogeneous populations with varied functional capacities. Based on these overall findings, we hypothesize that ML-DS is affected by interactions with ECs and the specific activity of ML-DS ECs

play a role in increased response to chemotherapy and reduced relapse rates observed with ML-DS patients. Understanding this mechanism will provide a deeper understanding of ML-DS. Although ML-DS patients respond favorably to AraC-base chemotherapy, those that relapse have dismal outcomes despite salvage therapies.

Thus, enhancing the already effective frontline treatments for ML-DS patients may further improve the EFS rates (already at ~90%) via reducing the risk of relapse. Hydroxyurea (HU) is an inhibitor of ribonucleotide reductase (RNR). RNR influences the abundance of the active AraC triphosphate metabolite AraCTP. Additionally, it was

recently reported that RNR inhibitors suppress sterile α-motif and histidine-aspartate domain-containing protein 1 (SAMHD1; a deoxynucleotide triphosphohydrolase), preventing SAMHD1 from hydrolyzing/inactivating AraCTP, resulting in enhanced AraC activity against non-DS AML. Our preliminary studies show that AraC-

resistant ML-DS cell line CMY has substantially increased SAMHD1 compared to AraC-sensitive ML-DS cell line CMK. Based on the literature and our preliminary data, we hypothesize that HU enhances AraC antileukemic activity against ML-DS. Our proposed studies will 1) determine the role of the DS bone marrow microenvironment

in ML-DS therapy responses and 2) use HU as an approach to enhance AraC activity against ML-DS cells. Studying the relationship between DS ECs and ML-DS and AraC sensitivity will improve our understanding of the mechanisms underlying the extremely high cure rates of children with ML-DS. Additionally, the development

of new AraC enhancing treatments for ML-DS patients may further improve OS rates of children with ML-DS.