Evidence for Increased Response to Induced Endoplasmic Reticulum Stress in Myeloid Cells in Acquired Aplastic Anemia.
Autoimmune response targeting the hematopoietic stem cells highlights the current understanding of acquired aplastic anemia (AAA) pathogenesis. Upregulation of the unfolded protein response is the cell's rejoinder to a variety of stresses, which either result in restoring homeostasis or cell death by increased expression of the transcription factor C/EBP homologous protein. We hypothesized that there is an inherent increased sensitivity to various cellular stressors, including the ones that target endoplasmic reticulum (ER) in AAA leading to a decreased proliferation and potentially contributing to susceptibility to autologous cytotoxicity. Using archived bone marrow aspirate samples, we demonstrate that the culture-expanded AAA myeloid cells have an increased response to ER stress induced by tunicamycin leading to decreased cell proliferation. Within the AAA myeloid samples, we show that the disease status, active versus response to therapy at the time of sampling does not alter the ER stress response. This is the first report, which provides evidence for an inherent defective stress control in the myeloid cells as a possible mechanism of evolution of the disease process in AAA.
*Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI †Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan ‡Molecular Therapeutics Program, Karmanos Cancer Institute §Pediatric Blood and Marrow Transplant Program, Children's Hospital of Michigan, Barbara Ann Karmanos Cancer Center, Detroit, MI.
Alpa
A
Sidhu
Michael U
MU
Callaghan
Manisha S
MS
Gadgeel
Steven A
SA
Buck
Andrew M
AM
Fribley
Süreyya
S
Savaşan
D000741:Anemia, Aplastic / Q000209:etiology* / Q000473:pathology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006801:Humans; D022423:Myeloid Cells / Q000473:pathology*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response
D000900:Anti-Bacterial Agents; D014415:Tunicamycin