IRAK1: oncotarget in MDS and AML

Myelodysplastic syndromes (MDS) are a collection of hematopoietic stem cell (HSC) disorders that consist of blood cytopenias, marrow dysplasia, and a predisposition to acute myeloid leukemia (AML). Approximately 30% of MDS patients go on to develop aggressive AML. MDS is fatal in a majority of patients as a result of marrow failure, immune dysfunction, and/or transformation to overt leukemia. Allogeneic HSC transplantation can be curative in MDS, but this option is suitable only in the small proportion of younger patients. Alterative treatment options for MDS include demethylating agents and immunomodulatory therapies. Disappointingly, the efficacy and durability of the remaining treatment options is variable. Targeted therapies have been effective in multiple myeloid diseases, and may also be effective in MDS by inhibiting the propagating clones. We recently identified IRAK1 as a therapeutic target for MDS and certain subsets of AML [1]. IRAK1 mRNA is overexpressed in ~20-30% of MDS patients. More importantly, IRAK1 protein is dramatically overexpressed and found within a hyperactivated state in a majority of MDS marrow sample examined. IRAK1 is a serine/threonine kinase that mediates signals from Toll-like receptor (TLR) and Interleukin-1 Receptor (IL1R) (Figure 1). Following receptor activation, IRAK1 becomes phosphorylated which then leads to recruitment of TRAF6. This interaction between IRAK1 and TRAF6 activates NF-κB, MAPK, AKT and other pathways. The molecular source of IRAK1 overexpression and/ or hyperactivation in MDS (or AML) is not conclusive (Figure 1) [2]. Overexpression of TLR or necessary cofactors in MDS clones may result in chronic IRAK1 activation even in the absence of infection [3, 4]. Small molecule inhibitors targeting IRAK1 (IRAK1/4 Inhibitor. Amgen Inc.) have been originally developed for autoimmune and inflammatory diseases. Given that IRAK1 is hyperactivated (i.e., phosphorylated) in MDS but not normal marrow cells, we reasoned that inhibiting this complex with a small molecule inhibitor would selectively suppress the MDS-propagating clones. We evaluated MDS and AML cell lines, as well as primary human MDS samples for sensitivity to the IRAK-Inh. MDS-propagating cells, and to a lesser extent AML cells, treated with IRAK-Inh exhibited a reduction in proliferation, progenitor function, and cell viability. To Editorial Material