Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype.
Homozygous loss of function of Runx1 (Runt-related transcription factor 1 gene) during murine development results in an embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis. In light of recent reports of disparate requirements for hematopoietic transcription factors during development as opposed to adult hematopoiesis, we used a conditional gene-targeting strategy to effect the loss of Runx1 function in adult mice. In contrast with the critical role of Runx1 during development, Runx1 was not essential for hematopoiesis in the adult hematopoietic compartment, though a number of significant hematopoietic abnormalities were observed. Runx1 excision had lineage-specific effects on B- and T-cell maturation and pronounced inhibition of common lymphocyte progenitor production. Runx1 excision also resulted in inefficient platelet production. Of note, Runx1-deficient mice developed a mild myeloproliferative phenotype characterized by an increase in peripheral blood neutrophils, an increase in myeloid progenitor populations, and extramedullary hematopoiesis composed of maturing myeloid and erythroid elements. These findings indicate that Runx1 deficiency has markedly different consequences during development compared with adult hematopoiesis, and they provide insight into the phenotypic manifestations of Runx1 deficiency in hematopoietic malignancies.
Growney
Joseph D
JD
Division of Hematology and Department of Pathology, Brigham and Women's Hospital, 1 Blackfan Circle, Boston, MA 02115, USA.
Shigematsu
Hirokazu
H
Li
Zhe
Z
Lee
Benjamin H
BH
Adelsperger
Jennifer
J
Rowan
Rebecca
R
Curley
David P
DP
Kutok
Jeffery L
JL
Akashi
Koichi
K
Williams
Ifor R
IR
Speck
Nancy A
NA
Gilliland
D Gary
DG
D000818:Animals; D001483:Base Sequence; D050676:Core Binding Factor Alpha 2 Subunit; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D004247:DNA