PMID- 29263441
OWN - NLM
STAT- MEDLINE
DCOM- 20190219
LR  - 20190320
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 32
IP  - 4
DP  - 2018 Apr
TI  - Age-related inflammatory bone marrow microenvironment induces ineffective 
      erythropoiesis mimicking del(5q) MDS.
PG  - 1023-1033
LID - 10.1038/leu.2017.326 [doi]
AB  - Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of 
      anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual 
      deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted 
      in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis 
      mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment 
      is important for the development of ineffective erythropoiesis in these mice. 
      Damage-associated molecular pattern molecules (DAMPs), whose levels increase in 
      ageing bone marrow, induced TNFalpha and IL-6 upregulation in myeloid-derived 
      suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, 
      we reveal that pathologic levels of TNFalpha and IL-6 inhibit erythroid colony 
      formation and differentially affect terminal erythropoiesis through reactive 
      oxygen species-induced caspase-3 activation and apoptosis. Treatment of the 
      mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted 
      the differentiation of MDSCs and ameliorated the inflammatory bone marrow 
      microenvironment, significantly rescued anemia and ineffective erythropoiesis. 
      Our study underscores the dual roles of the ageing microenvironment and genetic 
      abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.
FAU - Mei, Y
AU  - Mei Y
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
FAU - Zhao, B
AU  - Zhao B
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
FAU - Basiorka, A A
AU  - Basiorka AA
AD  - Cancer Biology PhD Program, H. Lee Moffitt Cancer Center and Research Institute 
      and the University of South Florida, Tampa, FL, USA.
FAU - Yang, J
AU  - Yang J
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
FAU - Cao, L
AU  - Cao L
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
AD  - Department of Hematology and Oncology, Children's Hospital of Soochow University, 
      Suzhou, China.
FAU - Zhang, J
AU  - Zhang J
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
FAU - List, A
AU  - List A
AD  - Cancer Biology PhD Program, H. Lee Moffitt Cancer Center and Research Institute 
      and the University of South Florida, Tampa, FL, USA.
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research 
      Institute, Tampa, FL, USA.
FAU - Ji, P
AU  - Ji P
AD  - Department of Pathology, Feinberg School of Medicine, Northwestern University, 
      Chicago, IL, USA.
LA  - eng
GR  - R01 DK102718/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20171116
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Aging/*genetics/pathology
MH  - Anemia/genetics/pathology
MH  - Animals
MH  - Apoptosis/genetics
MH  - Bone Marrow/*pathology
MH  - Cell Differentiation/genetics
MH  - Chromosome Deletion
MH  - Chromosomes, Human, Pair 5/*genetics
MH  - Erythropoiesis/*genetics
MH  - Humans
MH  - Inflammation/*genetics/*pathology
MH  - Interleukin-6/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myelodysplastic Syndromes/genetics/pathology
MH  - Tumor Microenvironment/*genetics
MH  - Tumor Necrosis Factor-alpha/genetics
MH  - Up-Regulation/genetics
PMC - PMC5886057
COIS- The authors declare no conflict of interest.
EDAT- 2017/12/22 06:00
MHDA- 2019/03/21 06:00
PMCR- 2018/04/05
CRDT- 2017/12/22 06:00
PHST- 2017/07/06 00:00 [received]
PHST- 2017/10/22 00:00 [revised]
PHST- 2017/10/26 00:00 [accepted]
PHST- 2017/12/22 06:00 [pubmed]
PHST- 2019/03/21 06:00 [medline]
PHST- 2017/12/22 06:00 [entrez]
PHST- 2018/04/05 00:00 [pmc-release]
AID - leu2017326 [pii]
AID - 10.1038/leu.2017.326 [doi]
PST - ppublish
SO  - Leukemia. 2018 Apr;32(4):1023-1033. doi: 10.1038/leu.2017.326. Epub 2017 Nov 16.