Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Britta Will, Li Zhou, Thomas O. Vogler, Susanna Ben-Neriah, Carolina Schinke, Roni Tamari, Yiting Yu, Tushar D. Bhagat, Sanchari Bhattacharyya, Laura Barreyro, Christoph Heuck, Yonkai Mo, Samir Parekh, Christine McMahon, Andrea Pellagatti, Jacqueline Boultwood, Cristina Montagna, Lewis Silverman, Jaroslaw Maciejewski, John M. GreallyB. Hilda Ye, Alan F. List, Christian Steidl, Ulrich Steidl, Amit Verma

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage-/CD34+/CD38-/CD90 +) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

Original languageEnglish (US)
Pages (from-to)2076-2086
Number of pages11
JournalBlood
Volume120
Issue number10
DOIs
StatePublished - Sep 6 2012

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Myelodysplastic Syndromes
Ports and harbors
Epigenomics
Stem Cells
Stem cells
Azacitidine
Hematopoietic Stem Cells
Genes
Myeloid Progenitor Cells
Granulocyte Precursor Cells
Chromosome Aberrations
Monocytes
Genome
Recurrence

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. / Will, Britta; Zhou, Li; Vogler, Thomas O.; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D.; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis; Maciejewski, Jaroslaw; Greally, John M.; Ye, B. Hilda; List, Alan F.; Steidl, Christian; Steidl, Ulrich; Verma, Amit.

In: Blood, Vol. 120, No. 10, 06.09.2012, p. 2076-2086.

Research output: Contribution to journalArticle

Will, B, Zhou, L, Vogler, TO, Ben-Neriah, S, Schinke, C, Tamari, R, Yu, Y, Bhagat, TD, Bhattacharyya, S, Barreyro, L, Heuck, C, Mo, Y, Parekh, S, McMahon, C, Pellagatti, A, Boultwood, J, Montagna, C, Silverman, L, Maciejewski, J, Greally, JM, Ye, BH, List, AF, Steidl, C, Steidl, U & Verma, A 2012, 'Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations', Blood, vol. 120, no. 10, pp. 2076-2086. https://doi.org/10.1182/blood-2011-12-399683
Will, Britta ; Zhou, Li ; Vogler, Thomas O. ; Ben-Neriah, Susanna ; Schinke, Carolina ; Tamari, Roni ; Yu, Yiting ; Bhagat, Tushar D. ; Bhattacharyya, Sanchari ; Barreyro, Laura ; Heuck, Christoph ; Mo, Yonkai ; Parekh, Samir ; McMahon, Christine ; Pellagatti, Andrea ; Boultwood, Jacqueline ; Montagna, Cristina ; Silverman, Lewis ; Maciejewski, Jaroslaw ; Greally, John M. ; Ye, B. Hilda ; List, Alan F. ; Steidl, Christian ; Steidl, Ulrich ; Verma, Amit. / Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. In: Blood. 2012 ; Vol. 120, No. 10. pp. 2076-2086.
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abstract = "Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage-/CD34+/CD38-/CD90 +) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92{\%} ± 4{\%}) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.",
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T1 - Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

AU - Will, Britta

AU - Zhou, Li

AU - Vogler, Thomas O.

AU - Ben-Neriah, Susanna

AU - Schinke, Carolina

AU - Tamari, Roni

AU - Yu, Yiting

AU - Bhagat, Tushar D.

AU - Bhattacharyya, Sanchari

AU - Barreyro, Laura

AU - Heuck, Christoph

AU - Mo, Yonkai

AU - Parekh, Samir

AU - McMahon, Christine

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

AU - Montagna, Cristina

AU - Silverman, Lewis

AU - Maciejewski, Jaroslaw

AU - Greally, John M.

AU - Ye, B. Hilda

AU - List, Alan F.

AU - Steidl, Christian

AU - Steidl, Ulrich

AU - Verma, Amit

PY - 2012/9/6

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N2 - Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage-/CD34+/CD38-/CD90 +) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

AB - Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage-/CD34+/CD38-/CD90 +) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

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