The Menin Tumor Suppressor Protein Is an Essential Oncogenic Cofactor for MLL-Associated Leukemogenesis

Abstract

The Mixed-Lineage Leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors. We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis. Furthermore, menin is essential for maintenance of MLL-associated but not other oncogene induced myeloid transformation. Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers.

Epigenetic regulations in hematopoietic Hox code

“…Overexpression of Cdx4 can activate a reporter gene driven by Cdx-protein-binding sites within a Hoxa9 gene. However, in a hematopoietic cell line, Cdx4-Hoxa9 biding is abolished by ablation of menin (Yan et al, 2006a), which is a cofactor of the histone methyltransferase-MLL complex (Yu et al, 1998;Yokoyama et al, 2004Yokoyama et al, , 2005. These results suggest that an active chromatin domain is a prerequisite for formation of the Cdx-Hox transcription initiating complex.…”

“…In accordance with chromatin domain, 5 0 HoxA cluster genes are sequentially activated in MLL-AF9-transduced hematopoietic cells. All 5 0 HoxA cluster genes (Hoxa5-13) are hyperexpressed in MLL-AF9 leukemia cells, whereas only Hoxa5-9 genes are activated in MLL-AF9 preleukemic cells (Kumar et al, 2004;Yokoyama et al, 2005;Yan et al, 2006a). These data suggest that 5 0 HoxA cluster genes are divided into at least two chromatin domains, whereas Hoxa5-9 genes are transcriptionally delimited from Hoxa10-13 by a speculated insulator.…”

“…It is easily concluded that chromosomal translocation results in development of MLL fusion oncogenes and accordingly, mis-expression of Hox genes. However, numerous studies have shown that overexpression of MLL fusion oncoproteins in normal ES and bone marrow cells first promotes nonmalignant expansion of myeloid precursors and Hox deregulation, and then is followed by accumulation of malignant cells (Dobson et al, 1999;Kumar et al, 2004;Yokoyama et al, 2005;Chen et al, 2006). The long latency in vivo and monoclonal nature of the leukemias suggest that secondary genetic transformation is required for the development of leukemia (Dobson et al, 1999;Johnson et al, 2003).…”

“…Increasing evidence suggests that Hox transcription factors play a definitive role in normal proliferation and differentiation of hematopoietic cells (Magli et al, 1997;Owens and Hawley, 2002). Recent discoveries revealed that the menin and MLL-containing histone methyltransferase complex is required for Hox gene-dependent proliferation and differentiation of hematopoietic progenitors and leukemia stem cells (Hess, 2004;Hughes et al, 2004;Milne et al, 2005;Yokoyama et al, 2005Yokoyama et al, , 2010Chen et al, 2006;Thiel et al, 2010). These studies have given emphasis to epigenetic regulations in Hox-dependent hematopoiesis and leukemogenesis.…”

RXR, un cofacteur essentiel à la transformation dans les leucémies aiguës promyélocytaires

“…De la même façon, le rôle clé d'une protéine partenaire a été mis en évidence dans les leucémies induites par les protéines de fusion impliquant MLL (mixed lineage leukemia) : la protéine Ménine est nécessaire à la transformation, ainsi qu'au maintien de la leucémie [31]. La dépendance d'une oncoprotéine de fusion à ses partenaires protéiques pourrait ainsi être un phénomène général dans le processus leucémogène.…”