Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Noemi A
NA
Zambetti
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Zhen
Z
Ping
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Si
S
Chen
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Keane J G
KJG
Kenswil
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Maria A
MA
Mylona
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Mathijs A
MA
Sanders
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Remco M
RM
Hoogenboezem
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Eric M J
EMJ
Bindels
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Maria N
MN
Adisty
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Paulina M H
PMH
Van Strien
Department of Internal Medicine, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Cindy S
CS
van der Leije
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam 1081HV, the Netherlands.
Theresia M
TM
Westers
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam 1081HV, the Netherlands.
Eline M P
EMP
Cremers
Department of Molecular Genetics, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Chiara
C
Milanese
Department of Molecular Genetics, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Pier G
PG
Mastroberardino
Department of Internal Medicine, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Johannes P T M
JPTM
van Leeuwen
Department of Internal Medicine, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Bram C J
BCJ
van der Eerden
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Ivo P
IP
Touw
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam 1105AZ, the Netherlands.
Taco W
TW
Kuijpers
Departments of Genetics and Radiation Oncology, Cancer Genomics Center, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
Roland
R
Kanaar
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam 1081HV, the Netherlands.
Arjan A
AA
van de Loosdrecht
Institute of Immunology, University of Münster, Münster 48149, Germany.
Thomas
T
Vogl
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands. Electronic address: m.h.g.raaijmakers@erasmusmc.nl.
Marc H G P
MHGP
Raaijmakers
D000818:Animals; D001855:Bone Marrow Diseases / Q000473:pathology; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D018450:Disease Progression; D010188:Exocrine Pancreatic Insufficiency / Q000473:pathology; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D019426:Integrases / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D008068:Lipomatosis / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D012307:Risk Factors; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D055153:Stem Cell Niche; D051193:Toll-Like Receptors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000069452:Pathogen-Associated Molecular Pattern Molecules; D011506:Proteins; D009418:S100 Proteins; C470521:SBDS protein, human; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases
S100A8; cancer; hematopoietic stem cell; inflammation; leukemia; mesenchymal; microenvironment; myelodysplastic syndrome (MDS); niche; shwachman-diamond syndrome