The inv(16) cooperates with ARF haploinsufficiency to induce acute myeloid leukemia.
The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML) and creates a chimeric fusion protein consisting of most of the runt-related X1 co-factor, core binding factor beta fused to the smooth muscle myosin heavy chain MYH11. Expression of the ARF tumor suppressor is regulated by runt-related X1, suggesting that the inv(16) fusion protein (IFP) may repress ARF expression. We established a murine bone marrow transplant model of the inv(16) in which wild type, Arf+/-, and Arf-/- bone marrow were engineered to express the IFP. IFP expression was sufficient to induce a myelomonocytic AML even when expressed in wild type bone marrow, yet removal of only a single allele of Arf greatly accelerated the disease, indicating that Arf is haploinsufficient for the induction of AML in the presence of the inv(16).
Moreno-Miralles
Isabel
I
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Pan
Ling
L
Keates-Baleeiro
Jennifer
J
Durst-Goodwin
Kristie
K
Yang
Chunying
C
Kim
Hyung-Gyoon
HG
Thompson
Mary Ann
MA
Klug
Christopher A
CA
Cleveland
John L
JL
Hiebert
Scott W
SW
D000483:Alleles; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014178:Translocation, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D025803:Tumor Suppressor Protein p14ARF; C471254:inv(16) fusion protein, human; D049452:Green Fluorescent Proteins; D004247:DNA