Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia.
The t(8;21)(q22;q22) is common in adult acute myeloid leukemia (AML). The RUNX1-ETO fusion protein that is expressed by this translocation is poorly leukemogenic and requires additional mutations for transformation. Loss of sex chromosome (LOS) is frequently observed in t(8;21) AML. In the present study, to evaluate whether LOS cooperates with t(8;21) in leukemogenesis, we first used a retroviral transduction/transplantation model to express RUNX1-ETO in hematopoietic cells from XO mice. The low frequency of leukemia in these mice suggests that the potentially critical gene for suppression of t(8;21) leukemia in humans is not conserved on mouse sex chromosomes. The gene encoding the GM-CSF receptor α subunit (CSF2RA) is located on X and Y chromosomes in humans but on chromosome 19 in mice. GM-CSF promotes myeloid cell survival, proliferation, and differentiation. To determine whether GM-CSF signaling affects RUNX1-ETO leukemogenesis, hematopoietic stem/progenitor cells that lack GM-CSF signaling were used to express RUNX1-ETO and transplanted into lethally irradiated mice, and a high penetrance of AML was observed in recipients. Furthermore, GM-CSF reduced the replating ability of RUNX1-ETO-expressing cells. These results suggest a possible tumor-suppressor role of GM-CSF in RUNX1-ETO leukemia. Loss of the CSF2RA gene may be a critical mutation explaining the high incidence of LOS associated with the t(8;21)(q22;q22) translocation.
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Shinobu
S
Matsuura
Ming
M
Yan
Miao-Chia
MC
Lo
Eun-Young
EY
Ahn
Stephanie
S
Weng
David
D
Dangoor
Mahan
M
Matin
Tsunehito
T
Higashi
Gen-Sheng
GS
Feng
Dong-Er
DE
Zhang
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012730:Sex Chromosomes / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; C572370:Csf2ra protein, mouse; D004268:DNA-Binding Proteins; C493598:MTG8 protein, mouse; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor