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T(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.

ABSTRACT: The t(8;21)(q22;q22) translocation is a non-random chromosomal abnormality frequently found in patients with acute myeloid leukemia (AML) with maturation (M2 subtype). We report here the cloning of a gene, named AML1, on chromosome 21 that was found to be rearranged in the leukemic cell DNAs from t(8;21) AML patients. The breakpoints in 16 out of 21 patients were clustered within a limited region of AML1, and detailed analysis in 3 patients revealed that the breakpoints occurred in the same intron of the gene. Sequencing of cDNA clones identified a long open reading frame encoding a 250-amino acid protein. Northern blot analysis detected four constant mRNA species in t(8;21) leukemic and normal cells; the largest species was more abundant in the leukemic cells than in normal cells. In addition, two mRNA species limited to the leukemic cells were found. These findings indicate that the AML1 gene may be involved in neoplastic transformation of AML with the t(8;21) translocation.

SUBMITTER: Miyoshi H

PROVIDER: S-EPMC52942 | biostudies-other | 1991 Dec

REPOSITORIES: biostudies-other

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t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.

Miyoshi H H Shimizu K K Kozu T T Maseki N N Kaneko Y Y Ohki M M

Proceedings of the National Academy of Sciences of the United States of America 19911201 23

The t(8;21)(q22;q22) translocation is a non-random chromosomal abnormality frequently found in patients with acute myeloid leukemia (AML) with maturation (M2 subtype). We report here the cloning of a gene, named AML1, on chromosome 21 that was found to be rearranged in the leukemic cell DNAs from t(8;21) AML patients. The breakpoints in 16 out of 21 patients were clustered within a limited region of AML1, and detailed analysis in 3 patients revealed that the breakpoints occurred in the same intr ...[more]

PMID: 1720541

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Project description:Backgroundt(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30-50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive.MethodsChromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO.ResultsHere we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells.ConclusionOur work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.

Dataset Information

T(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.

Publications

t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.

Similar Datasets

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