Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.
The MLL (Mixed Lineage Leukemia) gene is a common target for chromosomal translocations associated with human acute leukemias. These translocations result in a gain of MLL function by generating novel chimeric proteins containing the amino-terminus of MLL fused in-frame with one of 30 distinct partner proteins. Structure/function studies using an in vitro myeloid progenitor immortalization assay have revealed that at least four nuclear partner proteins contribute transcriptional effector properties to MLL to produce a range of chimeric transcription factors with leukemogenic potential. Mouse models suggest that expression of an MLL fusion protein is necessary but not sufficient for leukemogenesis. Interestingly, whilst all MLL fusion proteins tested so far phenocopy each other with respect to in vitro immortalization, the latency period required for the onset of acute leukemia in vivo is variable and partner protein dependent. We discuss potential mechanisms that may account for the ability of distinct MLL fusion proteins to promote short or long latency leukemogenesis.
Ayton
P M
PM
Department of Pathology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California, CA 94305, USA.
Cleary
M L
ML
D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D013329:Structure-Activity Relationship; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse