LPXN, a member of the paxillin superfamily, is fused to RUNX1 in an acute myeloid leukemia patient with a t(11;21)(q12;q22) translocation.
RUNX1 (previously AML1) is involved in multiple recurrent chromosomal rearrangements in hematological malignances. Recently, we identified a novel fusion between RUNX1 and LPXN from an acute myeloid leukemia (AML) patient with t(11;21)(q12;q22). This translocation generated four RUNX1/LPXN and one LPXN/RUNX1 chimeric transcripts. Two representative RUNX1/LPXN fusion proteins, RL and RLs, were both found to localize in the nucleus and could bring the CBFB protein into the nucleus like the wild-type RUNX1. Both fusion proteins inhibit the ability of RUNX1 to transactivate the CSF1R promoter, probably through competition for its target sequences. Unlike RL and RLs, the LPXN/RUNX1 fusion protein LR was found to localize in the cytoplasm. Thus, we believe it has little impact on the transcriptional activity of RUNX1. We also found that fusion proteins RL, RLs, LR, and wild-type LPXN could confer NIH3T3 cells with malignant transformation characteristics such as more rapid growth, the ability to form colonies in soft agar, and the ability to form solid tumors in the subcutaneous tissue of the BALB/c nude mice. Taken together, our data indicated that the RUNX1/LPXN and LPXN/RUNX1 fusion proteins may play important roles in leukemogenesis and that deregulation of cell adhesion pathways may be pathogenetically important in AML. Our study also suggests that LPXN may play an important role in carcinogenesis.
Dai
Hai-Ping
HP
Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, People's Republic of China.
Xue
Yong-Quan
YQ
Zhou
Jian-Wei
JW
Li
Ai-Ping
AP
Wu
Ya-Fang
YF
Pan
Jin-Lan
JL
Wang
Yong
Y
Zhang
Jun
J
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*
D015815:Cell Adhesion Molecules; D050676:Core Binding Factor Alpha 2 Subunit; C112251:LPXN protein, human; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; C493728:RUNX1 protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor