Immunoproteasome Inhibitors for the Treatment of MLL-AF4 ALL

Abstract

Acute lymphoblastic leukemia, ALL, is a cancer of the blood or bone marrow that develops from the uncontrolled proliferation of lymphocytes. One subtype of ALL is caused by a translocation involving the MLL gene, or mixed lineage leukemia gene on chromosome 11, known as MLL-r ALL. MLL-r ALL confers to a poor prognosis and only a 20-40% 5-year event free survival rate compared to an overall 68% 5-year survival rate for patients and 98% 5-year survival rate for pediatric patients that do not harbor this translocation. A translocation involving chromosomes 4 and 11 leads to the MLL-AF4 fusion protein, which is the driver of MLL-AF4 ALL, and accounts for 60% of MLL-r ALL. The standard treatment option for MLL-r ALL is standard induction chemotherapy which patients initially respond well to, but commonly relapse since MLL-r ALL has one of the highest relapse rates. Therefore, a new targeted treatment is needed for this deadly disease. In this project we are targeting the proteasome, specifically the immunoproteasome for the treatment of MLL-AF4 ALL. The proteasome is responsible for the degradation of damaged or misfolded proteins in order to maintain cellular homeostasis. Cancer cells are highly reliant on proteasomes due to the high production of misfolded proteins that will need to be degraded to reduce cellular stress and maintain homeostasis. The MLL-AF4 fusion protein promotes transcriptional elongation and DNA methylation, which increases its dependency on the proteasome. We have found that inhibiting the ability of the proteasome to degrade proteins increases cell stress and ultimately leads to apoptosis. There are two types of proteasomes: the constitutive proteasome, which is found in all tissues, and immunoproteasome, which is predominantly found in lymphoid tissues. The proteasome, both immune and constitutive, has 3 active sites that are responsible for protein degradation β5, β1, and β2. The β5 site, or β5i for immunoproteasomes, is the dominant site of protein degradation and the target of most proteasome inhibitors. B-cell ALL prominently expresses immunoproteasomes as does MLL-AF4 ALL. This provides a specific target for the treatment of MLL-AF4 ALL that can avoid the toxicities that are associated with FDA approved proteasome inhibitors. M3258, developed by MERCK KGaA, and ONX-0914 are the two immunoproteasome specific inhibitors used in this project. The goal of this project is to determine if the specific inhibition of immunoproteasomes can be a viable therapy option for MLL-AF4 ALL and the cause of sensitivity of MLL-AF4 ALL to proteasome inhibition.