Mapping of MN1 Sequences Necessary for Myeloid Transformation

Abstract

The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1’s in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12–228 (Δ12–228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Δ12–228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Δ12–228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.

Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate

“…9 MN1, an oncogene in murine hematopoiesis, is considered a candidate gene for sporadic meningioma 15 and is involved in human myeloid leukemia. [16][17][18] Mn1 is shown to be crucial in the development of membranous bones in the murine skull. In homozygous Mn1-knockout mice, cranial bone development is severely affected with decreased mineralization, hypoplasia or agenesis of several bones.…”

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

“…Two distinct subtypes of AML are negatively associated with high MN1 expression levels: AML with mutations in nucleophosmin 1 (NPM1c) (1)(2)(3)(4)(5) and AML with a translocation of the mixed lineage leukemia gene, MLL (4,6). The highest expression levels of MN1 have been reported in patients with an inversion of chromosome 16 (inv [16]), and 100% of inv(16) AML overexpress MN1 (4,6). In apparent contradiction to the poor outcome associated with high MN1 expression, inv (16) AML has a favorable prognosis.…”

“…The highest expression levels of MN1 have been reported in patients with an inversion of chromosome 16 (inv [16]), and 100% of inv(16) AML overexpress MN1 (4,6). In apparent contradiction to the poor outcome associated with high MN1 expression, inv (16) AML has a favorable prognosis. However, inv(16) AML represents only a small subgroup of MN1 hi AML.…”

“…MN1 overexpression in murine hematopoietic progenitors induces a rapidly fatal myeloid leukemia, reflecting the strong transforming ability of MN1 (6,(14)(15)(16). Forced expression of MN1 induces proliferation and a block in differentiation, mapped to the N-and C-terminus of MN1, respectively (13,16).…”

“…Forced expression of MN1 induces proliferation and a block in differentiation, mapped to the N-and C-terminus of MN1, respectively (13,16). The developmental window, during which MN1 is able to induce leukemia, is narrow and well defined; neither purified hematopoietic stem cells (HSCs) nor cells beyond the common myeloid progenitor (CMP) can serve as the cell of origin (14).…”