Abstract 2447: Lineage-specific metabolic reprogramming in BCR-ABL1-driven leukemia

Abstract

Abstract Background & Hypothesis: The serine-threonine liver kinase B1 (LKB1) activates AMP-activated protein kinase (AMPK) and negatively regulates aerobic glycoloysis (Warburg effect). LKB1 and AMPK have long been established as tumor suppressors, leading to clinical trials that test the efficacy of AMPK activators as cancer therapeutics. Paradoxically, we found that high expression levels of LKB1 and subunits of AMPK at diagnosis correlate with poor clinical outcome in patients with high risk B precursor acute lymphoblastic leukemia (ALL) (n = 207). These findings seem to contradict the historical notion of LKB1-AMPK as a tumor suppressor pathway, suggesting that the functions of LKB1-AMPK pathway may depend on cellular and genetic contexts. Results: Here, we focus on the role of LKB1 in BCR-ABL1-driven leukemia - chronic myeloid leukemia (CML) and B cell lineage Ph+ ALL. To do so, genetic mouse models for 4-hydroxytamoxifen (4-OHT)-inducible deletion of Lkb1 in BCR-ABL1-transformed hematopoietic stem and progenitor cells (CML-like) and B cell progenitors (Ph+ ALL) were developed. In agreement with previous findings in solid tumors, Cre-mediated Lkb1 deletion in CML-like cells resulted in enhanced proliferation. Unexpectedly, deletion of Lkb1 in Ph+ ALL cells led to apoptosis and cell cycle arrest. Moreover, Lkb1deletion delayed the onset of Ph+ ALL development as well as prolonged overall survival of transplant recipient mice in vivo. Consistent with the above observations, Arf, p53 and p27 levels were reduced in Lkb1-deficient CML cells, while Lkb1 deletion in Ph+ ALL cells up-regulated Arf, p53 and p27 levels. Decreases in glucose consumption and lactate production were also observed in Lkb1-deificient Ph+ ALL cells; however, increases in the levels of glucose consumed and lactate produced were detected in CML cells following Lkb1 deletion. Importantly, inhibition of AMPK using Compound C (an ATP-competitive inhibitor) resulted in apoptosis in patient-derived Ph+ ALL cells, while Compound C had no significant effects on the viability of a panel of lymphoma and multiple myeloma cell lines tested. Furthermore, patient-derived Ph+ ALL cells were resistant to treatment with various AMPK activators (metformin, phenformin and AICAR). Finally, Compound C showed synergistic responses in combination with Imatinib and different PI3K/AKT inhibitors (BKM120, AZD5363 and GSK690693) in Ph+ ALL. In vivo, Compound C in combination with BKM120, a PI3K inhibitor, exerted significantly more potent inhibitory effect on leukemia progression than each agent alone, prolonging the overall survival of recipient mice. Conclusions: Taken together, our findings demonstrate that LKB1 plays divergent roles in myeloid lineage CML and B cell lineage Ph+ ALL. While AMPK activators were shown to be effective against CML cells in previous studies, inhibiting the LKB1-AMPK pathway may provide a better therapeutic avenue for treatment of Ph+ ALL. Citation Format: Lai N. Chan, Seyedmehdi Shojaee, Christian Hurtz, Huimin Geng, Carina Ng, Behzad Kharabi, Markus Müschen. Lineage-specific metabolic reprogramming in BCR-ABL1-driven leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2447. doi:10.1158/1538-7445.AM2014-2447