title: Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations.
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.
authors: Albert Einstein College of Medicine, Bronx, NY, USA.
authors: Britta
authors: B
authors: Will
authors: Li
authors: L
authors: Zhou
authors: Thomas O
authors: TO
authors: Vogler
authors: Susanna
authors: S
authors: Ben-Neriah
authors: Carolina
authors: C
authors: Schinke
authors: Roni
authors: R
authors: Tamari
authors: Yiting
authors: Y
authors: Yu
authors: Tushar D
authors: TD
authors: Bhagat
authors: Sanchari
authors: S
authors: Bhattacharyya
authors: Laura
authors: L
authors: Barreyro
authors: Christoph
authors: C
authors: Heuck
authors: Yonkai
authors: Y
authors: Mo
authors: Samir
authors: S
authors: Parekh
authors: Christine
authors: C
authors: McMahon
authors: Andrea
authors: A
authors: Pellagatti
authors: Jacqueline
authors: J
authors: Boultwood
authors: Cristina
authors: C
authors: Montagna
authors: Lewis
authors: L
authors: Silverman
authors: Jaroslaw
authors: J
authors: Maciejewski
authors: John M
authors: JM
authors: Greally
authors: B Hilda
authors: BH
authors: Ye
authors: Alan F
authors: AF
authors: List
authors: Christian
authors: C
authors: Steidl
authors: Ulrich
authors: U
authors: Steidl
authors: Amit
authors: A
authors: Verma
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000008:administration & dosage; D016022:Case-Control Studies; D019070:Cell Lineage; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007621:Karyotyping; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D012008:Recurrence; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D001374:Azacitidine