Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions downstream of BTK, is a promising new target aimed at treating an aggressive BCR signaling-dependent subtype of non-Hodgkin’s lymphoma, known as ABC-DLBCL [1-3, 6]. Targeting this protein for small molecule inhibition may be effective in the treatment of BTKi-refractory CLL patients, as well as other leukemias, such as AML [19]. The effect of MALT1 or BTK inhibition on AML, CLL, and DLBCL cell proliferation was analyzed. Together with examination of protein expression in each cell line and the effect of MALT1 inhibition on cleavage of its downstream target RelB, it is supported that a clinical MALT1 inhibitor would be effective in slowing the growth of CLL, ABC-DLBCL, and AML tumors. Combinatorial experiments supported the hypothesis that combination treatment with MALT and BTK inhibitors could be efficacious at treating patients with relapsed or refractory CLL or ABC-DLBCL
