MEIS1 regulates an HLF–oxidative stress axis in MLL-fusion gene leukemia

Abstract

• Meis1 is required for the maintenance of MLL-fusion gene leukemia; HLF is a key downstream mediator of Meis1.• Meis1 and HLF restrict oxidative stress; induction of oxidative phosphorylation may be therapeutic in leukemia.Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1-deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a lowoxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment. (Blood. 2015;125(16):2544-2552 IntroductionReciprocal translocations of the 11q23 locus lead to acute leukemias of both myeloid and lymphoid lineages. These leukemias are usually resistant to conventional chemotherapies. The translocation generates an oncogenic fusion protein comprised of an amino terminus derived from MLL (now called KMT2A), the gene at 11q23, fused to a carboxy terminus derived from one of several different genes. Recent studies have revealed that these MLL-fusion proteins then join higher-order protein complexes containing various transcriptional activators and/or elongating factors such as DOT1L, PAFc, and p-TEFB. 1,2 Recruitment of these complexes to genomic loci was shown to be associated with chromatin modifications and subsequent changes in gene expression. 3 Regardless of the fusion partner involved in the translocation and of the consequential protein complex assembled, the downstream genes activated by the various MLL-fusion proteins are largely identical. Data from patientderived leukemia cells and from experimental models reveal that MLLfusion proteins upregulate the expression of posterior HOX-A genes and of the HOX cofactor MEIS1. [4][5][6] Further, retroviral overexpression of a Hox gene (with few exceptions) along with Meis1 in murine hematopoietic cells induces an aggressive leukemia in transplanted mice. 7,8 Thus, MLL-fusion protein induced upregulation of HOX and MEIS1 genes is considered central to the pathology of these leukemias.Studies to test the requirement of HOX-A and MEIS1 genes in MLL-fusion leukemias have yielded mixed results. Although shRNA knockdown of HOXA9 was shown to inhibit leukemia, mice lacking Hoxa9 protein developed leukemia induced...

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

“…24 It can be speculated thus, speculate that the unexpected lack of the C1q protein observed in neuT-C3KO tumors may be due to the lack of hypoxic-induced C1q mRNA transcription. Indeed, using the LASAGNA-Search tool 38 (http://biogrid.engr.uconn.edu/lasagna_search/) to perform binding sites searches on mouse C1q promoter, we confirmed the presence of binding sites specific for the transcriptional factors RelA, 39 Meis-1a, 40 AhR 41 , and Arnt, 42 known to be present on human C1q promoter and linked to hypoxia (GeneCards Ò , Human Gene Data base; http://www. genecards.org/cgi-bin/carddisp.pl?gene D C1QAandkeywords D c1qa).…”

Oxidative stress and hypoxia in normal and leukemic stem cells

“…Fourth, a recent study explored the molecular mechanisms responsible for the leukemogenetic effect of MLL-AF9 and showed an essential role of MEIS1, which induces a hepatic leukemia factor (HLF)-oxidative stress axis: MEIS1 expression in these leukemias limits the extent of oxidative stress and is essential for leukemia cell survival [103]. Consistent with this conclusion, MEIS1 knockdown in MLL-AF9 leukemic cells induces ROS production and inhibition of leukemic cell growth [105]. The analysis of the MLL-AF9 model showed also an essential role for MLL4 in maintaining a low oxidative stress, compatible with leukemic cell survival and growth: in fact, MLL4 knockout in these cells elicited a clear increase of ROS production and myeloid differentiation [105].…”

Deregulation of the HOXA9/MEIS1 axis in acute leukemia

“…The best characterized of these cofactors is MEIS1, which plays a synergistic causative role in leukemia with HOXA9 (14, 15). A recent study with Meis1 knockout/MLL-AF9 knockin murine model established that Meis1 is required for development of MLL-AF9 driven leukemias (67). This requirement is partially mediated through promoting a low oxidative environment established by direct regulation of HLF by Meis1.…”