C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

A. E. Marneth; K. H.M. Prange; A. S.A. Al Hinai; S. M. Bergevoet; N. Tesi; E. M. Janssen-Megens; B. Kim; N. Sharifi; M. L. Yaspo; J. Kuster; M. A. Sanders; E. C.G. Stoetman; J. Knijnenburg; T. C.J.M. Arentsen-Peters; C. M. Zwaan; H. G. Stunnenberg; M. M. Van Den Heuvel-Eibrink; T. Haferlach; M. Fornerod; J. H. Jansen; P. J.M. Valk; B. A. Van Der Reijden; J. H.A. Martens

doi:https://doi.org/10.1038/leu.2017.280

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

A. E. Marneth, K. H.M. Prange, A. S.A. Al Hinai, S. M. Bergevoet, N. Tesi, E. M. Janssen-Megens, B. Kim, N. Sharifi, M. L. Yaspo, J. Kuster, M. A. Sanders, E. C.G. Stoetman, J. Knijnenburg, T. C.J.M. Arentsen-Peters, C. M. Zwaan, H. G. Stunnenberg, M. M. Van Den Heuvel-Eibrink, T. Haferlach, M. Fornerod, J. H. JansenP. J.M. Valk, B. A. Van Der Reijden, J. H.A. Martens

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Abstract

Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

Original language	English
Pages (from-to)	828-836
Number of pages	9
Journal	Leukemia
Volume	32
Issue number	3
DOIs	https://doi.org/10.1038/leu.2017.280
Publication status	Published - 1 Mar 2018

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Marneth, A. E., Prange, K. H. M., Al Hinai, A. S. A., Bergevoet, S. M., Tesi, N., Janssen-Megens, E. M., Kim, B., Sharifi, N., Yaspo, M. L., Kuster, J., Sanders, M. A., Stoetman, E. C. G., Knijnenburg, J., Arentsen-Peters, T. C. J. M., Zwaan, C. M., Stunnenberg, H. G., Van Den Heuvel-Eibrink, M. M., Haferlach, T., Fornerod, M., ... Martens, J. H. A. (2018). C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. Leukemia, 32(3), 828-836. https://doi.org/10.1038/leu.2017.280

@article{c928c1c5226b44bb976bc20754425666,

title = "C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation",

abstract = "Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.",

author = "Marneth, {A. E.} and Prange, {K. H.M.} and {Al Hinai}, {A. S.A.} and Bergevoet, {S. M.} and N. Tesi and Janssen-Megens, {E. M.} and B. Kim and N. Sharifi and Yaspo, {M. L.} and J. Kuster and Sanders, {M. A.} and Stoetman, {E. C.G.} and J. Knijnenburg and Arentsen-Peters, {T. C.J.M.} and Zwaan, {C. M.} and Stunnenberg, {H. G.} and {Van Den Heuvel-Eibrink}, {M. M.} and T. Haferlach and M. Fornerod and Jansen, {J. H.} and Valk, {P. J.M.} and {Van Der Reijden}, {B. A.} and Martens, {J. H.A.}",

year = "2018",

month = mar,

day = "1",

doi = "https://doi.org/10.1038/leu.2017.280",

language = "English",

volume = "32",

pages = "828--836",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "3",

}

Marneth, AE, Prange, KHM, Al Hinai, ASA, Bergevoet, SM, Tesi, N, Janssen-Megens, EM, Kim, B, Sharifi, N, Yaspo, ML, Kuster, J, Sanders, MA, Stoetman, ECG, Knijnenburg, J, Arentsen-Peters, TCJM, Zwaan, CM, Stunnenberg, HG, Van Den Heuvel-Eibrink, MM, Haferlach, T, Fornerod, M, Jansen, JH, Valk, PJM, Van Der Reijden, BA & Martens, JHA 2018, 'C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation', Leukemia, vol. 32, no. 3, pp. 828-836. https://doi.org/10.1038/leu.2017.280

TY - JOUR

T1 - C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

AU - Marneth, A. E.

AU - Prange, K. H.M.

AU - Al Hinai, A. S.A.

AU - Bergevoet, S. M.

AU - Tesi, N.

AU - Janssen-Megens, E. M.

AU - Kim, B.

AU - Sharifi, N.

AU - Yaspo, M. L.

AU - Kuster, J.

AU - Sanders, M. A.

AU - Stoetman, E. C.G.

AU - Knijnenburg, J.

AU - Arentsen-Peters, T. C.J.M.

AU - Zwaan, C. M.

AU - Stunnenberg, H. G.

AU - Van Den Heuvel-Eibrink, M. M.

AU - Haferlach, T.

AU - Fornerod, M.

AU - Jansen, J. H.

AU - Valk, P. J.M.

AU - Van Der Reijden, B. A.

AU - Martens, J. H.A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

AB - Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

UR - http://www.scopus.com/inward/record.url?scp=85042935697&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/leu.2017.280

DO - https://doi.org/10.1038/leu.2017.280

M3 - Article

C2 - 28871137

SN - 0887-6924

VL - 32

SP - 828

EP - 836

JO - Leukemia

JF - Leukemia

IS - 3

ER -

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

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