MN1 overexpression is an important step in the development of inv(16) AML

Abstract

The gene encoding the transcriptional co-activator MN1 is the target of the reciprocal chromosome translocation (12;22) (p13;q12) in some patients with acute myeloid leukemia (AML). In addition, expression array analysis showed that MN1 was overexpressed in AML specified by inv(16), in some AML overexpressing ecotropic viral integration 1 site (EVI1) and in some AML without karyotypic abnormalities. Here we describe that mice receiving transplants of bone marrow (BM) overexpressing MN1 rapidly developed myeloproliferative disease (MPD). This BM also generated myeloid cell lines in culture. By mimicking the situation in human inv(16) AML, forced coexpression of MN1 and Cbfb-SMMHC rapidly caused AML in mice. These findings identify MN1 as a highly effective hematopoietic oncogene and suggest that MN1 overexpression is an important cooperative event in human inv(16) AML.

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

“…On the other hand, we found that 6 of 12 AML samples with high MN1 expression had no detectable HOXA9/MEIS1 expression. The highest MN1 expression level in this group was observed in 2 samples with inv(16) (AML 2 and 6), which has previously been shown to be universally associated with MN1 overexpression (4,6). Analysis of a well-annotated publicly available data set confirmed our results in a larger cohort of patients (30).…”

“…Our data strongly support further evaluation of DOT1L inhibition as a therapeutic strategy for this group of patients. Very high MN1 expression levels are also observed in inv(16) AML, which, in contrast to most other MN1 hi AML, is associated with a good prognosis (4,6). We found sensitivity to DOT1L inhibition in one cell line and 3 patient samples with inv (16).…”

“…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.…”

“…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).…”

Functional role of BAALC in leukemogenesis

“…Retroviral overexpression of human full-length MN1 in a murine model system induces rapid-onset AML. 8,9 We used murine BM cell lines immortalized by retroviral expression of Hoxa9 or NUP98HOXD13, and co-transduced these cells with full-length MN1 or a control vector as described before. 10 Baalc expression was not increased but rather decreased in MN1-expressing NUP98HOXD13 cells as compared with control transduced NUP98HOXD13 cells (Figure 1b).…”