AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia.
Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners.
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Chengqi
C
Lin
Edwin R
ER
Smith
Hidehisa
H
Takahashi
Ka Chun
KC
Lai
Skylar
S
Martin-Brown
Laurence
L
Florens
Michael P
MP
Washburn
Joan W
JW
Conaway
Ronald C
RC
Conaway
Ali
A
Shilatifard
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D018869:Heat-Shock Response; D011495:Histone-Lysine N-Methyltransferase; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000502:physiology; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000378:metabolism* / Q000502:physiology; D014178:Translocation, Genetic
C471348:AFF4 protein, human; D029721:Drosophila Proteins; C090862:ELL protein, human; D018840:HSP70 Heat-Shock Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D012097:Repressor Proteins; D035602:Transcriptional Elongation Factors; C097899:homeobox protein HOXA9; C069634:HOXA10 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D042925:Positive Transcriptional Elongation Factor B