MLL1

Official Full Name

lysine methyltransferase 2A

Organism

Homo sapiens

Gene ID

4297

Background

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

Synonyms

KMT2A; HRX; MLL; ALL1; GAS7; HTRX; MLL1; TRX1; ALL-1; CXXC7; HTRX1; MLL1A; WDSTS

Cat.No.	Product Name	Price
CSC-DC009563	Panoply™ Human MLL Knockdown Stable Cell Line	Inquiry
CSC-SC009563	Panoply™ Human MLL Over-expressing Stable Cell Line	Inquiry

Cat.No.	Product Name	Price
LV18324L	human MLL (NM_001197104) lentivirus particles	Inquiry
LV18325L	human MLL (NM_005933) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH191927	shRNA set against Human MLL(NM_001197104.1)	Inquiry
SHH331799	shRNA set against Rat LOC308990 (NM_001025001.1)	Inquiry
SHH342504	shRNA set against Human MLL (NM_005933.3)	Inquiry
SHH342508	shRNA set against Mouse MLL (NM_139311.2)	Inquiry
SHH342516	shRNA set against Mouse Mll1 (NM_001081049.1)	Inquiry
SHW012011	shRNA set against Danio rerio KMT2A (NM_001110279)	Inquiry

Cat.No.	Product Name	Price
CDFR003777	Rat LOC308990 cDNA Clone(NM_001025001.1)	Inquiry
MiUTR1H-06323	MLL miRNA 3'UTR clone	Inquiry
MiUTR1M-07149	MLL1 miRNA 3'UTR clone	Inquiry
MiUTR1R-03152	LOC308990 miRNA 3'UTR clone	Inquiry
CDCB173486	Danio rerio KMT2A ORF Clone (NM_001110279)	Inquiry
CDCH390112	Human MLL ORF clone(NM_005933.3)	Inquiry
CDCH390113	Mouse Mll1 ORF clone(NM_001081049.1)	Inquiry
CDCR370802	Rat LOC308990 ORF Clone(NM_001025001.1)	Inquiry

Detailed Information

The MLL gene encodes a histone methyltransferase protein, MLL1, which specifically methylates H3K4. MLL1 protein plays an important role in gene expression regulation, cell proliferation, developmental differentiation, etc. The dysfunction caused by its mutation leads to abnormal cell development or loss of function.

MLL1 Regulates the Expression of Hox Gene

The most important downstream regulatory gene of MLL1 is the Hox (Homeobox) family of genes. The Hox gene is a large class of genes with a homeobox, which plays an important role in regulating stem cell self-renewal and tissue formation. In general, MLL1 protein is regulating the expression of the Hox gene. In MLL knockout mice, the Hox gene was abnormally expressed after 9.5 days of embryonic phase, and the mouse died 10.5 days after the embryonic phase. The cause of death is the developmental defects of some neural crest-derived structures in the sacral arc, cranial nerve, and ganglion caused by abnormal expression of Hox gene. At the same time, MLL knockout mice also showed hematopoietic abnormalities, accompanied by down-regulation of some Hox genes (Hoxa7, Hoxa9, Hoxa10, Hoxa4). Therefore, MLL 1 protein plays a crucial role in the regulation of Hox genes during growth and development.

Mll1 Figure 1. Cyp33 regulation of the mammalian MLL1 histone methyltransferase protein. (Hanes, S. D. 2014)

The expression regulation of the Hox gene is dependent on the methyltransferase activity of the MLL1 protein, whereas mice that only excise the methyltransferase activity domain (SET domain) in the MLL gene are not lethal. This mutant mouse exhibits skeletal development defects and abnormal expression of some Hox genes, suggesting that MLL1 methyltransferase activity is important for maintaining the conformation of the chromosome and the expression of the Hox gene in vivo, but it is not the only decisive factor.

The important role of MLL1 in hematopoietic stem and progenitor cells is also related to the regulation of Hox gene expression. Although MLL1 has little effect on the mature hematopoietic system, it plays a crucial role in the early stages of blood cell development. Hematopoietic stem cells lacking the MLL gene are depleted due to abnormal cell cycle progression. MMP-deficient progenitor cells lacking proliferation and cytokine-induced cell cycle reduction, indicating that MLL1 plays a selective role in the hematopoietic system. The role of independence is mainly to maintain hematopoietic stem cells and promote the proliferation of progenitor cells.

MLL1 and Leukemia

Menin is a key protein that recruits wild-type MLL1 and MLL1 fusion proteins to target genes, and acts as an oncogene cofactor to up-regulate the transcription of specific genes and promote the development of leukemia induced by MLL1 fusion protein. Blocking the interaction between the MLL1 fusion protein and Menin will completely destroy the carcinogenic effect of the MLL1 fusion protein, so the site of action of MLL1 and Menin is an ideal drug target. Several laboratories have screened small molecule compounds that target the interaction of MLL1 and Menin and designed peptide analogs based on the MLL1 structure.

At present, some small molecule compounds have been screened and optimized to competitively inhibit the binding of MLL1. Preliminary cytological experiments show that these small molecule compounds have a significant inhibitory effect on the growth of MLL leukemia cells, and induce the death and differentiation of leukemia cells. Moreover, it down-regulated the expression of some genes related to carcinogenic activity, indicating that it is feasible to screen new therapeutic drugs by targeting MLL1 and Menin interactions.

References:

Hanes, S. D. . (2014). Prolyl isomerases in gene transcription. Biochimica et Biophysica Acta (BBA) - General Subjects,1850(10), 2017-2034.
Fang Cao., Elizabeth C. Townsend., Hacer Karatas., et al. (2014). Targeting mll1 h3k4 methyltransferase activity in mixed-lineage leukemia. Molecular Cell, 53(2), 247-261.
Xu, H. , Valerio, D. G. , Eisold, M. E. , Sinha, A. , Koche, R. P. , & Hu, W. , et al. (2016). Nup98 fusion proteins interact with the nsl and mll1 complexes to drive leukemogenesis. Cancer Cell,30(6), 863.

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