Direct and indirect targeting of MYC to treat acute myeloid leukemia

Abstract

PurposeAcute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification.MethodsWe performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1.ResultsshRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression.ConclusionsOur data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2766-z) contains supplementary material, which is available to authorized users.

Molecular dysfunctions in acute myeloid leukemia revealed by integrated analysis of microRNA and transcription factor

“…MYC is a basic transcription factor of the helix-loop-helixleucine zipper family, which is found upregulated in AML and has been shown to block the myeloid cell differentiation (33). Retroviral transduction of MYC into murine bone marrow cells results in AML development (33,54). Similarly, sustained expression of a human MYC transgene culminated in the formation of AML in mice (33).…”

“…Moreover, there were three pairs of miRNA→gene regulatory relationships (miR-126-5p and miR-126-3p represses pLK2 and miR-17-5p represses RuNx1) that have been experimentally confirmed in AML (30,31). Two TFs (NFKB1 and Myc) in this network have been reportedly associated with the development of AML (32,33). NFKB1 and Myc transcriptionally suppressed miR-29b-3p expression by binding to its promoter, and MYC was confirmed as a transcriptional repressor of miR-15a-5p, which were in accord with the same TF→miRNA regulatory relationships in our network (34,35).…”

“…Retroviral transduction of MYC into murine bone marrow cells results in AML development (33,54). Similarly, sustained expression of a human MYC transgene culminated in the formation of AML in mice (33). NFKB1 is a transcription factor that is constitutively activated in primitive human AML cells, while inhibition of NFKB1 displayed a rapid induction of apoptosis in AML cells (32,55).…”

“…Mice overexpressing miR-125b-5p causes a highly aggressive myeloid leukemia related to targeting the gene Lin28A (53). MYC is a basic transcription factor of the helix-loop-helixleucine zipper family, which is found upregulated in AML and has been shown to block the myeloid cell differentiation (33). Retroviral transduction of MYC into murine bone marrow cells results in AML development (33,54).…”

“…These findings are a preliminary reflection on the robustness of our network. Among these hub nodes, two hub miRNAs (miR-15a-5p and miR-125b-5p) and two hub TFs (Myc and NFKB1) have been previously implicated in AML (12,32,33,47). To further investigate the regulation of the four hub nodes, we extracted their subnetworks by including all their directly linked nodes in the miRNA-TF regulatory network (Fig.…”