The histone methyltransferase, Mixed-lineage leukemia-4 (MLL4), is a transcriptional coactivator of the BA-sensing nuclear receptor, Farnesoid-X-Receptor (FXR), and epigenetically upregulates FXR targets important for the regulation of BA levels, Small Heterodimer Partner (SHP) and Bile Salt Export Pump (BSEP).
The WHO 2008 classification further delineated three categories: associated with t(9;22)/BCR-ABL1 fusion gene, associated with KMT2A (mixed lineage leukemia) rearrangements, and nonotherwise specified.
Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells.
The comparison of MLL-AFF1 cases with the ABL1 group identified 477 genes being differentially expressed at the statistically significant level of p<0.05, with 296 and 181 genes up- and down-regulated, respectively, in the MLL-AFF1 cases.
Five translocations account for approximately 80% of MLL rearrangements: t(4;11)(q21;q23), AFF1/MLL; t(6;11)(q27;q23), MLLT4/MLL; t(9;11)(p22;q23), MLLT3/MLL; t(11;19)(q23;p13.1), MLL/ELL; and t(11;19)(q23;p13.3), MLL/MLLT1.
Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells.
In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17.
AF4 gene, frequently translocated with mixed-lineage leukemia (MLL) in childhood acute leukemia, encodes a putative transcriptional activator of the AF4/LAF4/FMR2 (ALF) protein family previously implicated in lymphopoiesis and Purkinje cell function in the cerebellum.
However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative.
We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells.
The findings demonstrated abnormal D-FISH results for 24 of 25 AFF1/MLL, 19 of 20 MLLT4/MLL, all 20 MLLT3/MLL, all 18 MLL/ELL, and all 20 MLL/MLLT1 samples, confirming the efficacy of these D-FISH assays in detecting these common MLL/partner translocations.
The most common MLL mutation in acute lymphoblastic leukemia is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in-frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins.
The comparison of MLL-AFF1 cases with the ABL1 group identified 477 genes being differentially expressed at the statistically significant level of p<0.05, with 296 and 181 genes up- and down-regulated, respectively, in the MLL-AFF1 cases.
Recently in Molecular Cell, Lin et al.(2010) showed that multiple MLL-fusion proteins implicated in mixed-lineage leukemia (MLL) associate with AFF4, ELLs, and the positive transcription elongation factor P-TEFb, providing evidence that the dysregulated gene expression in MLL patients is due to aberrant transcription elongation.
AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia.
AF4 gene, frequently translocated with mixed-lineage leukemia (MLL) in childhood acute leukemia, encodes a putative transcriptional activator of the AF4/LAF4/FMR2 (ALF) protein family previously implicated in lymphopoiesis and Purkinje cell function in the cerebellum.
The poor prognosis of lymphoblastic leukemia in children under 1 year of age is attributed largely to rearrangements involving the mixed lineage leukemia (mll, also known as all1, htrx, trx1, or hrx) gene that occur with increased frequency in this population.
Our data show that induction of 5-LO promoter activity by SMAD3/4 is MLL-dependent and that knockdown of the MLL complex component MEN1 attenuates the SMAD effect.
In B-precursor ALL, NG2 expression was significantly associated with a CD10(-)/CD34(-)/CD24(-)/CD65s(+)/CD15(+)/CD13(-)/CD33(-) phenotype and showed a sensitivity, specificity and positive predictive value of 0.89, 0.89, and 0.93 for MLL rearrangement, respectively.
Upon androgen stimulation, AR recruits the Protein kinase N1 (PKN1), which phosphorylates histone H3 at threonine 11, with subsequent recruitment of tryptophan, aspartic acid (WD) repeat-containing protein 5 (WDR5) and the su(var)3-9, enhancer of zeste, trithorax/mixed-lineage leukemia (SET1/MLL) histone methyltransferase complex to promote AR target gene activation and prostate cancer cell growth.