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The potential underlying mechanism of the leukemia caused byMLLâfusion and potential treatments
- Source :
- Molecular Carcinogenesis. 59:839-851
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- A majority of infant and pediatric leukemias are caused by the mixed-lineage leukemia gene (MLL) fused with a variety of candidates. Several underlying mechanisms have been proposed. One currently popular view is that truncated MLL1 fusion and its associated complex constitutively hijacks super elongation complex, including positive transcription elongation factor b, CDK9, and cyclin T1 complex and DOT1L, to enhance the expression of transcription factors that maintain or restore stemness of leukocytes, as well as prevent the differentiation of hematopoietic progenitor cells. An alternative emerging view proposes that MLL1-fusion promotes the recruitment of TATA binding protein and RNA polymerase II (Pol II) initiation complex, so as to increase the expression levels of target genes. The fundamental mechanism of both theories are gain of function for truncated MLL1 fusions, either through Pol II elongation or initiation. Our recent progress in transcription regulation of paused Pol II through JMJD5, JMJD6, and JMJD7, combined with the repressive role of H3K4me3 revealed by others, prompted us to introduce a contrarian hypothesis: the failure to shut down transcribing units by MLL-fusions triggers the transformation: loss of function of truncated MLL1 fusions coupled with the loss of conversion of H3K4me1 to H3K4me3, leading to the constitutive expression of transcription factors that are in charge of maintenance of hematopoietic progenitor cells, may trigger the transformation of normal cells into cancer cells. Following this track, a potential treatment to eliminate these fusion proteins, which may ultimately cure the disease, is proposed.
- Subjects :
- 0301 basic medicine
Cancer Research
Leukemia
Cyclin T1
Oncogene Proteins, Fusion
biology
RNA polymerase II
DOT1L
Fusion protein
Cell biology
Histones
03 medical and health sciences
Cell Transformation, Neoplastic
030104 developmental biology
0302 clinical medicine
030220 oncology & carcinogenesis
biology.protein
Transcriptional regulation
Animals
Humans
TATA-binding protein
P-TEFb
Molecular Biology
Transcription factor
Myeloid-Lymphoid Leukemia Protein
Subjects
Details
- ISSN :
- 10982744 and 08991987
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Molecular Carcinogenesis
- Accession number :
- edsair.doi.dedup.....4e088f31fad12a371bf1ef3576810acd