Biology:CLEC12A
 Generic protein structure example |
C-type lectin domain family 12 member A is a protein that in humans is encoded by the CLEC12A gene.[1]
This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. The protein encoded by this gene is a negative regulator of granulocyte and monocyte function. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL/CTLD superfamily members in the natural killer gene complex region on chromosome 12p13.[1]
CLEC12A, also known as MICL, is inhibitory C-type lectin-like receptor. It contains ITIM motif in cytoplasmic tail that can associate with signalling phosphatases SHP-1 and SHP-2.[2][3]
There are two types, human (hMICL) and murine (mMICL). Human MICL is expressed as a monomer primarily on myeloid cells, including granulocytes, monocytes, macrophages and dendritic cells.[2]
Murine MICL is expressed as dimer on granulocytes, monocytes but also on B lymfocytes and can be also found on NK cells surface in bone marrow.[4]
Use in therapy
In the immunotherapy of acute myeloid leukemia (AML), CLL-1 becomes one of the target due to its high expression in AML cells while being absent in normal hematopoietic stem cells. CLL-1 is also expressed on the surface of leukemic stem cells (LSC), which possesses the ability to indefinitely self-renew, produce plenty of leukemic cells and are associated with leukemia relapses.[5][6]
Scientists are working on various therapeutic approaches using CLL-1 as a target for AML. One of them is development of bispecific antibodies such as CD3/CLL-1 antibody. It can recruit unstimulated primary T cells in patients against cancer cells with CLL-1 on surface.[7]
Other way is development of CAR T cells specific for CLL-1 antigen. This principle showed efficient and specific anti-leukemia activity to AML cell lines from AML patients, as well as in mouse model.[8][9]
References
- ↑ 1.0 1.1 "Entrez Gene: CLEC12A C-type lectin domain family 12, member A". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=160364.
- ↑ 2.0 2.1 "Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation". European Journal of Immunology 36 (8): 2159–69. August 2006. doi:10.1002/eji.200535628. PMID 16838277.
- ↑ "Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes". The Journal of Biological Chemistry 279 (15): 14792–802. April 2004. doi:10.1074/jbc.m313127200. PMID 14739280.
- ↑ "Characterisation of murine MICL (CLEC12A) and evidence for an endogenous ligand". European Journal of Immunology 38 (4): 1157–63. April 2008. doi:10.1002/eji.200738057. PMID 18350551.
- ↑ "Therapeutic strategies targeting cancer stem cells". Cancer Science 107 (1): 5–11. January 2016. doi:10.1111/cas.12817. PMID 26362755.
- ↑ "Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia". World Journal of Stem Cells 6 (4): 473–84. September 2014. doi:10.4252/wjsc.v6.i4.473. PMID 25258669.
- ↑ "An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia". Blood 129 (5): 609–618. February 2017. doi:10.1182/blood-2016-08-735365. PMID 27908880.
- ↑ "Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia". International Journal of Molecular Sciences 18 (11): 2259. October 2017. doi:10.3390/ijms18112259. PMID 29077054.
- ↑ "Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1". Molecular Therapy 25 (9): 2202–2213. September 2017. doi:10.1016/j.ymthe.2017.05.024. PMID 28676343.
Further reading
- "C-type lectin-like domains". Current Opinion in Structural Biology 9 (5): 585–90. October 1999. doi:10.1016/S0959-440X(99)00009-3. PMID 10508765.
- "The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells". Blood 110 (7): 2659–66. October 2007. doi:10.1182/blood-2007-03-083048. PMID 17609428.
- "Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation". European Journal of Immunology 36 (8): 2159–69. August 2006. doi:10.1002/eji.200535628. PMID 16838277.
- "Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production". Blood 107 (4): 1459–67. February 2006. doi:10.1182/blood-2005-08-3264. PMID 16239426.
- "C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia". Cancer Research 64 (22): 8443–50. November 2004. doi:10.1158/0008-5472.CAN-04-1659. PMID 15548716.
- "KLRL1, a novel killer cell lectinlike receptor, inhibits natural killer cell cytotoxicity". Blood 104 (9): 2858–66. November 2004. doi:10.1182/blood-2004-03-0878. PMID 15238421.
- "Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes". The Journal of Biological Chemistry 279 (15): 14792–802. April 2004. doi:10.1074/jbc.M313127200. PMID 14739280.
- "Evolutionary analysis reveals collective properties and specificity in the C-type lectin and lectin-like domain superfamily". Proteins 53 (1): 44–55. October 2003. doi:10.1002/prot.10440. PMID 12945048.
External links
- Human CLEC12A genome location and CLEC12A gene details page in the UCSC Genome Browser.
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