Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Andres Jerez; Yuka Sugimoto; Hideki Makishima; Amit Verma; Anna M. Jankowska; Bartlomiej Przychodzen; Valeria Visconte; Ramon V. Tiu; Christine L. O'Keefe; Azim M. Mohamedali; Austin G. Kulasekararaj; Andrea Pellagatti; Kathy McGraw; Hideki Muramatsu; Alison R. Moliterno; Mikkael A. Sekeres; Michael A. McDevitt; Seiji Kojima; Alan List; Jacqueline Boultwood; Ghulam J. Mufti; Jaroslaw P. Maciejewski

doi:10.1182/blood-2011-12-397620

Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Andres Jerez, Yuka Sugimoto, Hideki Makishima, Amit Verma, Anna M. Jankowska, Bartlomiej Przychodzen, Valeria Visconte, Ramon V. Tiu, Christine L. O'Keefe, Azim M. Mohamedali, Austin G. Kulasekararaj, Andrea Pellagatti, Kathy McGraw, Hideki Muramatsu, Alison R. Moliterno, Mikkael A. Sekeres, Michael A. McDevitt, Seiji Kojima, Alan List, Jacqueline BoultwoodGhulam J. Mufti, Jaroslaw P. Maciejewski

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Abstract

Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. (Blood. 2012;119(25):6109-6117)

Original language	English
Pages (from-to)	6109-6117
Number of pages	9
Journal	Blood
Volume	119
Issue number	25
Early online date	2 May 2012
DOIs	https://doi.org/10.1182/blood-2011-12-397620
Publication status	Published - 21 Jun 2012

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Jerez, A., Sugimoto, Y., Makishima, H., Verma, A., Jankowska, A. M., Przychodzen, B., Visconte, V., Tiu, R. V., O'Keefe, C. L., Mohamedali, A. M., Kulasekararaj, A. G., Pellagatti, A., McGraw, K., Muramatsu, H., Moliterno, A. R., Sekeres, M. A., McDevitt, M. A., Kojima, S., List, A., ... Maciejewski, J. P. (2012). Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood, 119(25), 6109-6117. https://doi.org/10.1182/blood-2011-12-397620

@article{b98b14b4281f48a7aa63052117372ed9,

title = "Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis",

abstract = "Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. (Blood. 2012;119(25):6109-6117)",

author = "Andres Jerez and Yuka Sugimoto and Hideki Makishima and Amit Verma and Jankowska, {Anna M.} and Bartlomiej Przychodzen and Valeria Visconte and Tiu, {Ramon V.} and O'Keefe, {Christine L.} and Mohamedali, {Azim M.} and Kulasekararaj, {Austin G.} and Andrea Pellagatti and Kathy McGraw and Hideki Muramatsu and Moliterno, {Alison R.} and Sekeres, {Mikkael A.} and McDevitt, {Michael A.} and Seiji Kojima and Alan List and Jacqueline Boultwood and Mufti, {Ghulam J.} and Maciejewski, {Jaroslaw P.}",

year = "2012",

month = jun,

day = "21",

doi = "10.1182/blood-2011-12-397620",

language = "English",

volume = "119",

pages = "6109--6117",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "25",

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Jerez, A, Sugimoto, Y, Makishima, H, Verma, A, Jankowska, AM, Przychodzen, B, Visconte, V, Tiu, RV, O'Keefe, CL, Mohamedali, AM, Kulasekararaj, AG, Pellagatti, A, McGraw, K, Muramatsu, H, Moliterno, AR, Sekeres, MA, McDevitt, MA, Kojima, S, List, A, Boultwood, J, Mufti, GJ & Maciejewski, JP 2012, 'Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis', Blood, vol. 119, no. 25, pp. 6109-6117. https://doi.org/10.1182/blood-2011-12-397620

TY - JOUR

T1 - Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

AU - Jerez, Andres

AU - Sugimoto, Yuka

AU - Makishima, Hideki

AU - Verma, Amit

AU - Jankowska, Anna M.

AU - Przychodzen, Bartlomiej

AU - Visconte, Valeria

AU - Tiu, Ramon V.

AU - O'Keefe, Christine L.

AU - Mohamedali, Azim M.

AU - Kulasekararaj, Austin G.

AU - Pellagatti, Andrea

AU - McGraw, Kathy

AU - Muramatsu, Hideki

AU - Moliterno, Alison R.

AU - Sekeres, Mikkael A.

AU - McDevitt, Michael A.

AU - Kojima, Seiji

AU - List, Alan

AU - Boultwood, Jacqueline

AU - Mufti, Ghulam J.

AU - Maciejewski, Jaroslaw P.

PY - 2012/6/21

Y1 - 2012/6/21

N2 - Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. (Blood. 2012;119(25):6109-6117)

AB - Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. (Blood. 2012;119(25):6109-6117)

U2 - 10.1182/blood-2011-12-397620

DO - 10.1182/blood-2011-12-397620

M3 - Article

SN - 0006-4971

VL - 119

SP - 6109

EP - 6117

JO - Blood

JF - Blood

IS - 25

ER -

Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

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