GABP is necessary for stem/progenitor cell maintenance and myeloid differentiation in human hematopoiesis and chronic myeloid leukemia.
Maintenance of hematopoietic stem cells and their potential to give rise to progenitors of differentiated lymphoid and myeloid cells are accomplished by a network of regulatory processes. As a part of this network, the heteromeric transcription factor GA-binding protein (GABP) plays a crucial role in self-renewal of murine hematopoietic and leukemic stem cells. Here, we report the consequences of functional impairment of GABP in human hematopoietic and in leukemic stem/progenitor cells. Ectopic overexpression of a dominant-negative acting GABP mutant led to impaired myeloid differentiation of CD34(+) hematopoietic stem/progenitor cells obtained from healthy donors. Moreover, drastically reduced clonogenic capacity of leukemic stem/progenitor cells isolated from bone marrow aspirates of chronic myeloid leukemia (CML) patients underlines the importance of GABP on stem/progenitor cell maintenance and confirms the relevance of GABP for human myelopoiesis in healthy and diseased states.
Institute of Human Genetics, Hannover Medical School, Hannover, Germany. Electronic address: manukjan.georgi@mh-hannover.de.
Georgi
G
Manukjan
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Tim
T
Ripperger
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Letizia
L
Venturini
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Michael
M
Stadler
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Gudrun
G
Göhring
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Axel
A
Schambach
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Brigitte
B
Schlegelberger
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Doris
D
Steinemann
D000328:Adult; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051268:GA-Binding Protein Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000633:toxicity; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D038042:Myelopoiesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D018952:Antigens, CD34; D051268:GA-Binding Protein Transcription Factor; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate
CML/chronic myeloid leukemia; GABP; Hematopoietic stem cell; Leukemic stem cell; Transcription factor