Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression.
CD56(high) acute myeloid leukemias (AMLs) have a poor prognosis, but it has been unclear how CD56 expression is controlled and how it relates to clinical aggressiveness. We show that CD56 expression on AML cells correlates with an abnormal expression pattern of runt-related transcription factor 1 (RUNX1) isoforms. Whereas full-length p48 RUNX1 (p48) up-regulated CD56 in AML cells, 3 previously unknown shorter RUNX1 isoforms, p38a, p30, and p24, suppressed CD56 expression. Both p48 and CD56 induced nuclear translocation of nuclear factor (NF)-kappaB and increased bcl2L12 expression, and inhibition of this pathway by small inhibitory RNA-mediated p48 knock down or NF-kappaB blockade substantially increased apoptosis in CD56(+) AML cell lines. These findings indicate the potential for new therapy of CD56(high) AML by suppression of the "overactive" RUNX1/CD56/NF-kappaB signaling pathway(s).
Gattenloehner
Stefan
S
Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany. stefan.gattenloehner@mail.uni-wuerzburg.de
Chuvpilo
Sergei
S
Langebrake
Claudia
C
Reinhardt
Dirk
D
Müller-Hermelink
Hans-Konrad
HK
Serfling
Edgar
E
Vincent
Angela
A
Marx
Alexander
A
D000208:Acute Disease; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D019002:CD56 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D015723:Gene Library; D005799:Genes, Dominant; D006801:Humans; D007124:Immunoenzyme Techniques; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases; D014407:Tumor Cells, Cultured
D017304:Annexin A5; C430100:BCL2L12 protein, human; D019002:CD56 Antigen; D050676:Core Binding Factor Alpha 2 Subunit; D009124:Muscle Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C493728:RUNX1 protein, human; D008156:Luciferases; D012260:Ribonucleases