Acute Myeloid Leukemia (AML) is a heterogeneous disease where many distinct functional mutations have been identified. While mutations in FLT3, NRAS, NPM1, and IDH genes have been well characterized in de novo AML, a subset of AML associated with leukemic transformation of chronic myeloproliferative neoplasms (MPNs) are enriched in mutated JAK2 and PTPN11. MPNs are a set of disorders characterized by the chronic and abnormal overproduction of blood cells which can ultimately progress to AML. Targeted therapy against mutated JAK2 and PTPN11 with small molecule inhibitors against the JAK-STAT and RAS-ERK pathways, respectively, are being actively investigated in AML. However, acquired resistance and non-durable responses are already being demonstrated in monotherapy treatment. Thus, AML that has arisen from leukemic transformation of MPNs remains an area of unmet medical need. This need is underscored by the fact that these patients suffer from poor outcomes and low response rates to standard chemotherapy. Together, these results indicate the need for rational combinations in this population.

In this study, we sought to better define the dependencies of AML cells on BCL-2 family members by screening AML cell lines with selective small molecule inhibitors to the BCL-2 family members. The screen revealed that the majority of AML cell lines depend on BCL-2, or BCL-2 together with MCL1 for survival. Intriguingly, a subset of AML cell lines is exquisitely sensitive to BCL-xL inhibition. Treating these cell lines with BCL-xL-selective inhibitor or with navitoclax, a dual BCL2/BCL-xL inhibitor induces apoptosis. These BCL-xL inhibitor-sensitive cell lines express high levels of BCL-xL, but not BCL-2 and MCL1. Genomic analysis of BCL-xL inhibitor-sensitive AML cell lines revealed that this subset is also enriched in JAK2V16F and PTPN11 mutations. We further demonstrate positive combination effect between BCL-xL inhibitor or navitoclax with JAK inhibitor (ruxolitinb) and two MEK inhibitors (trametinib and AZD6244) in cell lines with JAK2V16F and PTPN11 mutations, respectively. Together, these results demonstrate the potential utility of a BCL-xL inhibition as a combination partner in JAK2 and PTPN11 mutated cancers. Importantly, JAK2 and PTPN11 mutations in addition to expression of BCL-xL, BCL-2, and MCL1 could also be further tested as potential biomarkers for the utility of BCL-xL inhibition based treatments for patients with these mutations.

Citation Format: Richard J. Bellin, Valerie Hilgenberg, Relja Popovic, Tamar Uziel, Lloyd T. Lam. JAK2 and PTPN11 mutations as potential biomarkers for BCL-xL inhibition as monotherapy and in combination therapy for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3812. doi:10.1158/1538-7445.AM2017-3812