MN1-TEL, the product of the t(12;22) in human myeloid leukemia, immortalizes murine myeloid cells and causes myeloid malignancy in mice

Abstract

MN1-TEL is the product of the recurrent t(12;22)(p12;q11) associated with human myeloid malignancies. MN1-TEL functions as an activated transcription factor, exhibiting weak transforming activity in NIH3T3 fibroblasts that depends on the presence of a functional TEL DNA-binding domain, the N-terminal transactivating sequences of MN1 and C-terminal sequences of MN1. We determined the transforming activity of MN1-TEL in mouse bone marrow (BM) by using retroviral transfer. MN1-TEL-transduced BM showed increased selfrenewal capacity of primitive progenitors in vitro, and prolonged in vitro culture of MN1-TEL-expressing BM produced immortalized myeloid, interleukin (IL)-3/stem cell factor-dependent cell lines with a primitive morphology. Transplantation of such cell lines into lethally irradiated mice rescued them from irradiation-induced death and resulted in the contribution of MN1-TEL-expressing cells to all hematopoietic lineages, underscoring the primitive nature of these cells and their capacity to differentiate in vivo. Three months after transplantation, all mice succumbed to promonocytic leukemia. Transplantation of freshly MN1-TEL-transduced BM into lethally irradiated mice also caused acute myeloid leukemia within 3 months of transplantation. We infer that MN1-TEL is a hematopoietic oncogene that stimulates the growth of hematopoietic cells, but depends on secondary mutations to cause leukemia in mice.

MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML

“…5 If MN1/TEL was retrovirally overexpressed, AML developed within 3 months, even if the DNA binding domain of TEL was mutated. 38 Our data suggest that MN1 by itself is sufficient to cause leukemia. It is one of the most potent hematopoietic oncogenes described today.…”

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia

“…3 Expression of MN1-TEL in the mouse hematopoietic system by a conditional knock-in strategy resulted in the formation of T-cell lymphomas as well as AML after a long latency, suggesting that MN1-TEL, similar to MLL-X fusions, is essential but not sufficient to induce the disease. [4][5][6] Gene expression profiling studies of a large number of human leukemia samples showed that MN1 is deregulated in cases with alterations at 3q26 leading to ecotropic virus integration-1 (EVI1) overexpression. 7 In addition, elevated MN1 expression has been associated with the presence of inv16 leading to a core-binding factor-b/MYH11 fusion.…”

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

“…Examples are the t(4;12)(q11-q12;p13) involving the CHIC2 gene, and the t(5;12)(q31;p13) the ACS2 gene, 14 the t(7;12)(q36;p13) involving the HLXB9 gene, [15][16][17] the t(9;12)(q11;p13) the PAX5 gene 18,19 and the t(12;22)(p13;q11) the MN1 gene. [20][21][22] These are all recurrent translocations but only some of the fusions are in frame.…”