Functional inactivation of P53 as a potential mechanism of MLL leukemogenesis.
In multiple types of acute leukemia,a portion of the MLL protein is fused to a variety of other unrelated proteins. The activity of leukemic MLL fusions is believed to be directly contributing to the conversion of normal bone marrow cells into leukemic cancer cells. However, the mechanism of this process has not been fully elucidated. We have recently found that the MLL leukemic fusions can abolish the activity of P53 tumor suppressor protein that actively guards against the appearance of cancer by instructing damaged cells to self-destruct. In contrast to the vast majority of cancers where p53 gene is mutated, very few p53 mutations have been found in leukemias. Our findings suggest that leukemic fusions contribute to disease progression, at least in part, by suppressing the function of P53, which,if proven,may present a novel opportunity to re-activating the P53 pathway in leukemic cells thereby identifying a rational therapeutic approach for managing leukemias where MLL fusions are detected.
Wiederschain
Dmitri
D
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Yuan
Zhi-min
ZM
D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
C497422:KMT2A protein, human; C470550:MLL-AF10 fusion protein, human; C472772:MLL-ELL fusion protein, human; D015514:Oncogene Proteins, Fusion; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase