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Cited by 171Pluripotent Stem Cells ResearchAcute Myeloid Leukemia ResearchGenomic variations and chromosomal abnormalities

Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells

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Kotini, Andriana G, Chang, Chan-Jung, Boussaad, Ibrahim, Delrow, Jeffrey J, Dolezal, Emily K, Nagulapally, Abhinav B, Perna, Fabiana, Fishbein, Gregory A +7 more·2015·Nature Biotechnology
DOI 10.1038/nbt.3178PMC PMC4464949
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Abstract

Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.

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  1. [1]Beroukhim R The landscape of somatic copy-number alteration across human cancers Nature 463 899 905 2010 20164920 PMC2826709
  2. [3]Weischenfeldt J Symmons O Spitz F Korbel JO Phenotypic impact of genomic structural variation: insights from and for human disease Nat Rev Genet 14 125 138 2013 23329113
  3. [5]Li J PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer Science 275 1943 1947 1997 9072974
  4. [6]Berger AH Knudson AG Pandolfi PP A continuum model for tumour suppression Nature 476 163 169 2011 21833082 PMC3206311
  5. [7]Solimini NL Recurrent hemizygous deletions in cancers may optimize proliferative potential Science 337 104 109 2012 22628553 PMC4027969
  6. [9]Jerez A Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis Blood 119 6109 6117 2012 22553315 PMC3383019
  7. [10]Soldner F Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations Cell 146 318 331 2011 21757228 PMC3155290
  8. [11]Grskovic M Javaherian A Strulovici B Daley GQ Induced pluripotent stem cells--opportunities for disease modelling and drug discovery Nat Rev Drug Discov 10 915 929 2011 22076509
  9. [12]Papapetrou EP Genomic safe harbors permit high beta-globin transgene expression in thalassemia induced pluripotent stem cells Nat Biotechnol 29 73 78 2011 21151124 PMC3356916
  10. [13]Papapetrou EP Sadelain M Generation of transgene-free human induced pluripotent stem cells with an excisable single polycistronic vector Nat Protoc 6 1251 1273 2011 21886095
  11. [14]Walter MJ Clonal architecture of secondary acute myeloid leukemia N Engl J Med 366 1090 1098 2012 22417201 PMC3320218
  12. [15]Sturgeon CM Ditadi A Clarke RL Keller G Defining the path to hematopoietic stem cells Nat Biotechnol 31 416 418 2013 23657396
  13. [16]Kennedy M T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures Cell Rep 2 1722 1735 2012 23219550
  14. [17]Flores-Figueroa E Gutierrez-Espindola G Guerrero-Rivera S Pizzuto-Chavez J Mayani H Hematopoietic progenitor cells from patients with myelodysplastic syndromes: in vitro colony growth and long-term proliferation Leuk Res 23 385 394 1999 10229325
  15. [18]Sato T Kim S Selleri C Young NS Maciejewski JP Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome Leukemia 12 1187 1194 1998 9697872
  16. [19]Amps K Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage Nat Biotechnol 29 1132 1144 2011 22119741 PMC3454460
  17. [20]Narva E High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity Nat Biotechnol 28 371 377 2010 20351689
  18. [21]Li LB Trisomy correction in down syndrome induced pluripotent stem cells Cell Stem Cell 11 615 619 2012 23084023 PMC3705773
  19. [22]Lewandoski M Martin GR Cre-mediated chromosome loss in mice Nat Genet 17 223 225 1997 9326948
  20. [23]Matsumura H Targeted chromosome elimination from ES-somatic hybrid cells Nat Methods 4 23 25 2007 17086180
  21. [24]Davoli T Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome Cell 155 948 962 2013 24183448 PMC3891052
  22. [25]Xue W A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions Proc Natl Acad Sci U S A 109 8212 8217 2012 22566646 PMC3361457
  23. [26]Ebert BL Identification of RPS14 as a 5q- syndrome gene by RNA interference screen Nature 451 335 339 2008 18202658 PMC3771855
  24. [27]Starczynowski DT Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype Nat Med 16 49 58 2010 19898489
  25. [29]Nikoloski G Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes Nat Genet 42 665 667 2010 20601954
  26. [30]Lindsley RC Ebert BL The biology and clinical impact of genetic lesions in myeloid malignancies Blood 2013 23954890
  27. [33]Shih AH Abdel-Wahab O Patel JP Levine RL The role of mutations in epigenetic regulators in myeloid malignancies Nat Rev Cancer 12 599 612 2012 22898539
  28. [34]Gonzalez F An iCRISPR platform for rapid, multiplexable, and inducible genome editing in human pluripotent stem cells Cell Stem Cell 15 215 226 2014 24931489 PMC4127112
  29. [35]Young MA Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells Cell Stem Cell 10 570 582 2012 22542160 PMC3348423
  30. [36]Abyzov A Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells Nature 492 438 442 2012 23160490 PMC3532053
  31. [38]Le Beau MM Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases Blood 88 1930 1935 1996 8822909
  32. [39]Dohner K Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders Blood 92 4031 4035 1998 9834205
  33. [40]Chen C MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia Cancer Cell 25 652 665 2014 24794707 PMC4206212
  34. [42]Carette JE Haploid genetic screens in human cells identify host factors used by pathogens Science 326 1231 1235 2009 19965467
  35. [43]White JK Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes Cell 154 452 464 2013 23870131 PMC3717207
  36. [44]Bolze A Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia Science 340 976 978 2013 23579497 PMC3677541
  37. [45]Hosono N Recurrent genetic defects on chromosome 7q in myeloid neoplasms Leukemia 28 1348 1351 2014 24429498 PMC8694066
  38. [46]Singh H Putative RNA-splicing gene LUC7L2 on 7q34 represents a candidate gene in pathogenesis of myeloid malignancies Blood cancer journal 3 e117 2013 23708642 PMC3674458
  39. [49]Cibulskis K Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples Nat Biotechnol 31 213 219 2013 23396013 PMC3833702
  40. [50]Papapetrou EP Korkola JE Sadelain M A genetic strategy for single and combinatorial analysis of miRNA function in mammalian hematopoietic stem cells Stem Cells 28 287 296 2010 19911427

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Authors
Kotini, A. G., Chang, C.-J., Boussaad, I., Delrow, J. J., Dolezal, E. K., Nagulapally, A. B., Perna, F., Fishbein, G. A., Klimek, V. M., Hawkins, R. D., Huangfu, D., Murry, C. E., Graubert, T., Nimer, S. D., & Papapetrou, E. P.
Affiliations
  • Tisch Cancer Institute (US)
  • University of Washington (US)
  • Fred Hutch Cancer Center (US)
  • University of Miami (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of California, Los Angeles (US)
  • Massachusetts General Hospital (US)
Corresponding author
Papapetrou, Eirini P
ORCID
Venue
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Published
2015-03-23
Volume
33
Issue
6
Pages
646-655
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
DOI
10.1038/nbt.3178
PMC
PMC4464949
OpenAlex
W2074191990
Cited by
171
References
10
Citations by year
2026: 7 · 2025: 9 · 2024: 13 · 2023: 8 · 2022: 11 · 2021: 21 · 2020: 14 · 2019: 13 · 2018: 18 · 2017: 25 · 2016: 21 · 2015: 10 · 2013: 1
FWCI
10.72
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Sidney Kimmel Foundation for Cancer Research
  • University of Washington
  • Sidney Kimmel Foundation
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL121570)
  • National Cancer Institute (P30CA 15704, P30CA008748, P30CA015704, R01CA166835)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R00DK087923, R01DK096239)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
chromosome 7q deletion, myelodysplastic syndrome, induced pluripotent stem cells, haploinsufficiency, hematopoietic differentiation, hemizygosity, chromosomal abnormalities
MeSH terms
Animals, Chromosome Deletion, Chromosomes, Human, Pair 7, Genetic Engineering, Humans, Karyotyping, Myelodysplastic Syndromes, Mice, Induced Pluripotent Stem Cells

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