REVISITING THE NF-KAPPAB AXIS IN MLL-REARRANGED LEUKEMIA
2019
NF-κB has been broadly implicated in the survival of acute myeloid leukemia (AML) through distinct mechanisms. MLL fusion oncoprotein (MLL-FP) leukemia is thought to require NF-κB activity based on several publications. First, RelA collaborates with MLL1/MLL-FPs to sustain leukemogenic genetic programs. Second, the IL-1/IRAK signaling axis has been connected to a mechanism of MLL1/MLL-FP competition. Third, our recent data shows that NFκB-dependent target genes are globally reduced by MLL1/MLL2 deletion in murine and human AML. To address the role of the NF-κB pathway in MLL-FP-driven AML, we pursued several orthogonal approaches. Pharmacologic inhibition of IRAK1/4 activity reduces MLL-FP AML proliferation and delays leukemia progression in mice. Inhibiting IRAK1/4 blocks phosphorylation of the ubiquitin ligase UBE2O, preventing degradation of WT MLL1 protein. Stabilization of MLL1 is then thought to impede genome-wide MLL-FP chromatin occupancy and activation of oncogenic programs. To address the ability of MLL1 to compete with MLL-FP in AML, we developed a doxycycline-dependent MLL1 inducible model. Increasing WT MLL1 during MLL-AF9-driven leukemogenesis did not affect disease phenotype, latency, or penetrance. Furthermore, WT MLL1 levels did not affect the sensitivity of murine or human MLL-FP cells to IRAK1/4 inhibition. Ongoing experiments focus on the survival role of IL1/IRAK/UBE2O signaling in MLL1-deficient AML. Furthermore, to investigate the potential of MLL2 inhibition as a therapeutic strategy in AML and to study the connection to NF-κB, we expressed a series of peptides designed to hinder MLL2’s chromatin occupancy. The impact and specificity of these peptides was compared to MLL2 loss in several systems. These approaches collectively aim to identify the most effective strategy for targeting survival pathways in MLL-rearranged AML.
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