The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription

Wely, Karel H. M. van; Meester-Smoor, Magda A.; Janssen, Maarten; Aarnoudse, Albert Jan; Grosveld, Gerard; Zwarthoff, Ellen C.

doi:10.1038/sj.onc.1210382

Cited by 26 publications

(18 citation statements)

References 26 publications

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“…RAR/RXR recruits MN1 via the transcriptional coactivator p300/CBP. High expression of MN1 is associated with ATRA resistance in vitro and in human non-APL AML [14]. Heuser et al [13] also found that non-APL AML patients with low MN1 expression may benefit from treatment with ATRA.…”

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confidence: 96%

Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent

Shen

Hong

et al. 2008

Leukemia & Lymphoma

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Acute myeloid leukemia (AML) is characterized by a block of terminal differentiation of hematopoietic precursors and the repression of normal hematopoiesis by expanding immature blasts. AMLs are frequently associated with specific chromosomal translocations, resulting in the generation of chimeric genes. These genes encode chimeric transcription factors, which possess chromatin-modeling activity and deregulate the transcription of specific target genes [1].The use of all-trans retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (APL). The great majority of patients treated with ATRA as a single agent will experience a relapse within a few months. Nevertheless, when used in combination with conventional chemotherapy, the efficacy of ATRA increases dramatically, improving the long-term survival of APL patients to 75% [2]. In non-APL AML, the effects of ATRA are less clear. The majority of non-APL AML blast cells are sensitive to ATRA in vitro, but a considerable proportion of the cells are resistant [3]. This stresses the need for more knowledge about the molecular mechanisms of ARTA and the demand for tools to predict ARTA sensitivity. A distinct subset of AML, making up *10% of all AML cases, is characterized by a t(8;21)(q22;q22) translocation and, morphologically, by the presence of myeloblasts, showing maturation in the neutrophil lineage. The t(8;21) juxtaposes the RUNX1 gene on chromosome 21 with the CBFT1 gene on chromosome 8, generating the AML1-ETO fusion transcription factor. We now present four patients with AML treated with ATRA alone, who were initially misdiagnosed as APL according to the FrenchAmerican-British (FAB) classification.Case 1: In July 2007, a 25-year-old man with a fever and cough was admitted to other hospital. Peripheral blood counts showed hemoglobin (Hb) 65 g/L, white blood cells (WBC) 23.3610 9 /L, blood platelet cells (plts) 69610 9 /L. Bone marrow examination revealed a hypercellularity with 16% myeloblasts and 52% abnormal promyelocytes in the existence of Auer rods, large granules packed in cytoplasm and nuclei irregular in size and shape. Diagnosis was made as APL based on FAB classification. The patient received arsenic trioxide (10 mg/day) for 30 days, WBC was 15.8610 9 /L with normal platelet count, and the level of promyelocytes in bone marrow was reduced to 18.4%. Then, he was admitted to our hospital and continued to receive arsenic trioxide. At this point, the diagnosis was changed from APL to t(8;21) AML according to karyotype analysis, flow cytometric immunophenotyping of bone marrow cells and reverse transcription polymerase chain reaction (RT-PCR) ( Table I). Interphase fluorescence in situ hybridization (FISH) showed 96.7% of AML1-ETO fusion gene in bone marrow cells but failed to demonstrate the presence of PML-RARa fusion gene. Myeloblasts in peripheral blood disappeared, and promyelocytes decreased from 18.4% to 9.16% by the 50th day after arsenic trioxide treatment was initiated. However, FISH analysis for AML1-E...

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confidence: 96%

Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent

Shen

Hong

et al. 2008

Leukemia & Lymphoma

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“…Exactly how MN1 contributes to leukemogenesis is still not fully understood. A dominant negative effect on RAR/TEL signaling has been described for the MN1-TEL fusion (11), but this mechanism may not apply to MN1 overexpression. Importantly, MN1 has little structural similarity to any other protein (12,13).…”

Section: Introductionmentioning

confidence: 99%

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

Riedel¹,

Haladyna²,

Bezzant³

et al. 2016

Journal of Clinical Investigation

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“…These translocations can result in the chimeric fusion of MN1 and TEL, the partial disruption of TEL, or no disruption in these genes. The oncogenic activities of MN1-TEL include the upregulation of HOXA9 and the inhibition of RAR-RXR-mediated transcription (Kawagoe et al, 2005;van Wely et al, 2007). The biological significance of the partial disruption of TEL caused by t(12;22) is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The fusion protein of MN1-TEL has oncogenic activities through the upregulation of HOXA9 and the inhibition of RAR-RXR-mediated transcription (Kawagoe et al, 2005;van Wely et al, 2007). However, some patients with t(12;22) did not have a chimeric MN1-TEL, and the implications of t(12;22) lacking MN1-TEL are not understood.…”

Section: Introductionmentioning

confidence: 98%

Establishment of a novel human myeloid leukemia cell line, AMU‐AML1, carrying t(12;22)(p13;q11) without chimeric MN1‐TEL and with high expression of MN1

Gotou¹,

Hanamura²,

Nagoshi³

et al. 2011

Genes Chromosomes & Cancer

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In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping. Fluorescent in situ hybridization analysis indicated that the chromosomal breakpoint in band 12p13 was in the sequence from the 5 0 untranslated region to intron 1 of TEL and that the chromosomal breakpoint in band 22q11 was in the 3 0 untranslated region of MN1. The chimeric transcript and protein of MN1-TEL could not be detected by reverse-transcriptase polymerase chain reaction or Western blot analysis. However, the MN1 gene was amplified to three copies detected by array comparative genomic hybridization analysis, and the expression levels of the MN1 transcript and protein were high in AMU-AML1 cells when compared with other cell lines with t(12;22)(p13;q11-12). Our data showed that AMU-AML1 cells contain t(12;22)(p13;q11.2) without chimeric fusion of MN1 and TEL. The AMU-AML1 cells gained MN1 copies and had high expression levels of MN1. Thus, the AMU-AML1 cell line is useful for studying the biological consequences of t(12;22)(p13;q11.2) lacking chimeric MN1-TEL.

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The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription

Cited by 26 publications

References 26 publications

Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent

Acute myeloid leukemia in four patients with t(8;21) treated with all-trans retinoic acid as a single agent

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

Establishment of a novel human myeloid leukemia cell line, AMU‐AML1, carrying t(12;22)(p13;q11) without chimeric MN1‐TEL and with high expression of MN1

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