Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion

Parvathy Venugopal; Peer Arts; Lucy C. Fox; Annet Simons; Devendra K. Hiwase; Peter G. Bardy; Annette Swift; David M. Ross; Lize F.D. van Vulpen; Arjan Buijs; Kelly L. Bolton; Bartlomiej Getta; Eliska Furlong; Tina Carter; Ingrid Krapels; Marlijn Hoeks; Adila Al Kindy; Farah Al Kindy; Sonja de Munnik; Pamela Evans; Mahalia S.B. Frank; Adam M. Bournazos; Sandra T. Cooper; Thuong Thi Ha; Matilda R. Jackson; Luis Arriola-Martinez; Kerry Phillips; Yvonne Brennan; Madhura Bakshi; Karen Ambler; Song Gao; Karin S. Kassahn; Rosalie Kenyon; Kevin Hung; Milena Babic; Alan McGovern; Lesley Rawlings; Cassandra Vakulin; Lucas Dejong; Rema Fathi; Simon McRae; Nicholas Myles; Dariusz Ladon; Marjolijn Jongmans; Roland P. Kuiper; Nicola K. Poplawski; Pasquale Barbaro; Piers Blombery; Anna L. Brown; Christopher N. Hahn; Hamish S. Scott

doi:10.1182/bloodadvances.2023012331

Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion

Parvathy Venugopal, Peer Arts, Lucy C. Fox, Annet Simons, Devendra K. Hiwase, Peter G. Bardy, Annette Swift, David M. Ross, Lize F.D. van Vulpen, Arjan Buijs, Kelly L. Bolton, Bartlomiej Getta, Eliska Furlong, Tina Carter, Ingrid Krapels, Marlijn Hoeks, Adila Al Kindy, Farah Al Kindy, Sonja de Munnik, Pamela EvansMahalia S.B. Frank, Adam M. Bournazos, Sandra T. Cooper, Thuong Thi Ha, Matilda R. Jackson, Luis Arriola-Martinez, Kerry Phillips, Yvonne Brennan, Madhura Bakshi, Karen Ambler, Song Gao, Karin S. Kassahn, Rosalie Kenyon, Kevin Hung, Milena Babic, Alan McGovern, Lesley Rawlings, Cassandra Vakulin, Lucas Dejong, Rema Fathi, Simon McRae, Nicholas Myles, Dariusz Ladon, Marjolijn Jongmans, Roland P. Kuiper, Nicola K. Poplawski, Pasquale Barbaro, Piers Blombery, Anna L. Brown, Christopher N. Hahn, Hamish S. Scott

College of Medicine and Public Health

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Abstract

Pathogenic germ line heterozygous variants in MECOM (myelodysplastic syndrome[MDS]1 and EVI1 complex locus) are associated with an autosomal dominant bone marrow failure (BMF) disorder characterized by radioulnar synostosis (RUS) often accompanied by amegakaryocytic thrombocytopenia (RUSAT2; Mendelian Inheritance in Man number 616738). MECOM is a transcription factor that is essential for hematopoietic stem cell self-renewal, and the loss of MECOM decreases absolute long term hematopoietic stem cell numbers.1 Several differentially spliced transcripts are encoded by the MECOM locus resulting in MDS1, MDS1-EVI1, and EVI1 isoforms. It has been demonstrated that these isoforms are involved in their own transcriptional regulation through distinct promoter regions and have an effect on the maintenance and transformation of hematopoietic stem and progenitor cell populations.

Original language	English
Pages (from-to)	3437-3443
Number of pages	7
Journal	Blood Advances
Volume	8
Issue number	13
DOIs	https://doi.org/10.1182/bloodadvances.2023012331
Publication status	Published - 9 Jul 2024

Keywords

MECOM
myelodysplastic syndrome
EVI1 complex locus
autosomal dominant bone marrow failure
somatic genetics
Pathogenic germ line heterozygous variants
clonal hematopoiesis
phenotype expansion

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Venugopal, P., Arts, P., Fox, L. C., Simons, A., Hiwase, D. K., Bardy, P. G., Swift, A., Ross, D. M., van Vulpen, L. F. D., Buijs, A., Bolton, K. L., Getta, B., Furlong, E., Carter, T., Krapels, I., Hoeks, M., Al Kindy, A., Al Kindy, F., de Munnik, S., ... Scott, H. S. (2024). Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion. Blood Advances, 8(13), 3437-3443. https://doi.org/10.1182/bloodadvances.2023012331

@article{fe7b55f8a0b649828a0fe868675943ba,

title = "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion",

abstract = "Pathogenic germ line heterozygous variants in MECOM (myelodysplastic syndrome[MDS]1 and EVI1 complex locus) are associated with an autosomal dominant bone marrow failure (BMF) disorder characterized by radioulnar synostosis (RUS) often accompanied by amegakaryocytic thrombocytopenia (RUSAT2; Mendelian Inheritance in Man number 616738). MECOM is a transcription factor that is essential for hematopoietic stem cell self-renewal, and the loss of MECOM decreases absolute long term hematopoietic stem cell numbers.1 Several differentially spliced transcripts are encoded by the MECOM locus resulting in MDS1, MDS1-EVI1, and EVI1 isoforms. It has been demonstrated that these isoforms are involved in their own transcriptional regulation through distinct promoter regions and have an effect on the maintenance and transformation of hematopoietic stem and progenitor cell populations.",

keywords = "MECOM, myelodysplastic syndrome, EVI1 complex locus, autosomal dominant bone marrow failure, somatic genetics, Pathogenic germ line heterozygous variants, clonal hematopoiesis, phenotype expansion",

author = "Parvathy Venugopal and Peer Arts and Fox, {Lucy C.} and Annet Simons and Hiwase, {Devendra K.} and Bardy, {Peter G.} and Annette Swift and Ross, {David M.} and {van Vulpen}, {Lize F.D.} and Arjan Buijs and Bolton, {Kelly L.} and Bartlomiej Getta and Eliska Furlong and Tina Carter and Ingrid Krapels and Marlijn Hoeks and {Al Kindy}, Adila and {Al Kindy}, Farah and {de Munnik}, Sonja and Pamela Evans and Frank, {Mahalia S.B.} and Bournazos, {Adam M.} and Cooper, {Sandra T.} and Ha, {Thuong Thi} and Jackson, {Matilda R.} and Luis Arriola-Martinez and Kerry Phillips and Yvonne Brennan and Madhura Bakshi and Karen Ambler and Song Gao and Kassahn, {Karin S.} and Rosalie Kenyon and Kevin Hung and Milena Babic and Alan McGovern and Lesley Rawlings and Cassandra Vakulin and Lucas Dejong and Rema Fathi and Simon McRae and Nicholas Myles and Dariusz Ladon and Marjolijn Jongmans and Kuiper, {Roland P.} and Poplawski, {Nicola K.} and Pasquale Barbaro and Piers Blombery and Brown, {Anna L.} and Hahn, {Christopher N.} and Scott, {Hamish S.}",

year = "2024",

month = jul,

day = "9",

doi = "10.1182/bloodadvances.2023012331",

language = "English",

volume = "8",

pages = "3437--3443",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "Elsevier B.V.",

number = "13",

}

Venugopal, P, Arts, P, Fox, LC, Simons, A, Hiwase, DK, Bardy, PG, Swift, A, Ross, DM, van Vulpen, LFD, Buijs, A, Bolton, KL, Getta, B, Furlong, E, Carter, T, Krapels, I, Hoeks, M, Al Kindy, A, Al Kindy, F, de Munnik, S, Evans, P, Frank, MSB, Bournazos, AM, Cooper, ST, Ha, TT, Jackson, MR, Arriola-Martinez, L, Phillips, K, Brennan, Y, Bakshi, M, Ambler, K, Gao, S, Kassahn, KS, Kenyon, R, Hung, K, Babic, M, McGovern, A, Rawlings, L, Vakulin, C, Dejong, L, Fathi, R, McRae, S, Myles, N, Ladon, D, Jongmans, M, Kuiper, RP, Poplawski, NK, Barbaro, P, Blombery, P, Brown, AL, Hahn, CN & Scott, HS 2024, 'Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion', Blood Advances, vol. 8, no. 13, pp. 3437-3443. https://doi.org/10.1182/bloodadvances.2023012331

TY - JOUR

T1 - Unraveling facets of MECOM-associated syndrome

T2 - somatic genetic rescue, clonal hematopoiesis, and phenotype expansion

AU - Venugopal, Parvathy

AU - Arts, Peer

AU - Fox, Lucy C.

AU - Simons, Annet

AU - Hiwase, Devendra K.

AU - Bardy, Peter G.

AU - Swift, Annette

AU - Ross, David M.

AU - van Vulpen, Lize F.D.

AU - Buijs, Arjan

AU - Bolton, Kelly L.

AU - Getta, Bartlomiej

AU - Furlong, Eliska

AU - Carter, Tina

AU - Krapels, Ingrid

AU - Hoeks, Marlijn

AU - Al Kindy, Adila

AU - Al Kindy, Farah

AU - de Munnik, Sonja

AU - Evans, Pamela

AU - Frank, Mahalia S.B.

AU - Bournazos, Adam M.

AU - Cooper, Sandra T.

AU - Ha, Thuong Thi

AU - Jackson, Matilda R.

AU - Arriola-Martinez, Luis

AU - Phillips, Kerry

AU - Brennan, Yvonne

AU - Bakshi, Madhura

AU - Ambler, Karen

AU - Gao, Song

AU - Kassahn, Karin S.

AU - Kenyon, Rosalie

AU - Hung, Kevin

AU - Babic, Milena

AU - McGovern, Alan

AU - Rawlings, Lesley

AU - Vakulin, Cassandra

AU - Dejong, Lucas

AU - Fathi, Rema

AU - McRae, Simon

AU - Myles, Nicholas

AU - Ladon, Dariusz

AU - Jongmans, Marjolijn

AU - Kuiper, Roland P.

AU - Poplawski, Nicola K.

AU - Barbaro, Pasquale

AU - Blombery, Piers

AU - Brown, Anna L.

AU - Hahn, Christopher N.

AU - Scott, Hamish S.

PY - 2024/7/9

Y1 - 2024/7/9

N2 - Pathogenic germ line heterozygous variants in MECOM (myelodysplastic syndrome[MDS]1 and EVI1 complex locus) are associated with an autosomal dominant bone marrow failure (BMF) disorder characterized by radioulnar synostosis (RUS) often accompanied by amegakaryocytic thrombocytopenia (RUSAT2; Mendelian Inheritance in Man number 616738). MECOM is a transcription factor that is essential for hematopoietic stem cell self-renewal, and the loss of MECOM decreases absolute long term hematopoietic stem cell numbers.1 Several differentially spliced transcripts are encoded by the MECOM locus resulting in MDS1, MDS1-EVI1, and EVI1 isoforms. It has been demonstrated that these isoforms are involved in their own transcriptional regulation through distinct promoter regions and have an effect on the maintenance and transformation of hematopoietic stem and progenitor cell populations.

AB - Pathogenic germ line heterozygous variants in MECOM (myelodysplastic syndrome[MDS]1 and EVI1 complex locus) are associated with an autosomal dominant bone marrow failure (BMF) disorder characterized by radioulnar synostosis (RUS) often accompanied by amegakaryocytic thrombocytopenia (RUSAT2; Mendelian Inheritance in Man number 616738). MECOM is a transcription factor that is essential for hematopoietic stem cell self-renewal, and the loss of MECOM decreases absolute long term hematopoietic stem cell numbers.1 Several differentially spliced transcripts are encoded by the MECOM locus resulting in MDS1, MDS1-EVI1, and EVI1 isoforms. It has been demonstrated that these isoforms are involved in their own transcriptional regulation through distinct promoter regions and have an effect on the maintenance and transformation of hematopoietic stem and progenitor cell populations.

KW - MECOM

KW - myelodysplastic syndrome

KW - EVI1 complex locus

KW - autosomal dominant bone marrow failure

KW - somatic genetics

KW - Pathogenic germ line heterozygous variants

KW - clonal hematopoiesis

KW - phenotype expansion

UR - http://www.scopus.com/inward/record.url?scp=85198533774&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/1164601

UR - http://purl.org/au-research/grants/NHMRC/76777

UR - http://purl.org/au-research/grants/NHMRC/2023357

U2 - 10.1182/bloodadvances.2023012331

DO - 10.1182/bloodadvances.2023012331

M3 - Letter

C2 - 38662475

AN - SCOPUS:85198533774

SN - 2473-9529

VL - 8

SP - 3437

EP - 3443

JO - Blood Advances

JF - Blood Advances

IS - 13

ER -

Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion

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Keywords

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