The AF4.MLL fusion protein is capable of inducing ALL in mice without requirement of MLL.AF4.
The chromosomal translocation t(4;11)(q21;q23) is the most frequent genetic aberration of the human MLL gene, resulting in high-risk acute lymphoblastic leukemia (ALL). To elucidate the leukemogenic potential of the fusion proteins MLL.AF4 and AF4.MLL, Lin(-)/Sca1(+) purified cells (LSPCs) were retrovirally transduced with either both fusion genes or with MLL.AF4 or AF4.MLL alone. Recipients of AF4.MLL- or double-transduced LSPCs developed pro-B ALL, B/T biphenotypic acute leukemia, or mixed lineage leukemia. Transplantation of MLL.AF4- or mock-transduced LSPCs did not result in disease development during an observation period of 13 months. These findings indicate that the expression of the AF4.MLL fusion protein is capable of inducing acute lymphoblastic leukemia even in the absence of the MLL.AF4 fusion protein. In view of recent findings, these results may imply that t(4;11) leukemia is based on 2 oncoproteins, providing an explanation for the very early onset of disease in humans.
Bursen
Adelheid
A
Institute of Pharmaceutical Biology/ZAFES/DCAL, Goethe-University of Frankfurt, Biocenter, Frankfurt, Germany.
Schwabe
Karen
K
Rüster
Brigitte
B
Henschler
Reinhard
R
Ruthardt
Martin
M
Dingermann
Theo
T
Marschalek
Rolf
R
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008297:Male; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D014178:Translocation, Genetic
C489900:Aff1 protein, mouse; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse