CLEC12A

C-type lectin domain family 12 member A is a protein that in humans is encoded by the CLEC12A gene.[5]

CLEC12A
Identifiers
AliasesCLEC12A, CLL-1, CLL1, DCAL-2, MICL, CD371, C-type lectin domain family 12 member A
External IDsOMIM: 612088 MGI: 3040968 HomoloGene: 51378 GeneCards: CLEC12A
Gene location (Human)
Chr.Chromosome 12 (human)[1]
Band12p13.31Start9,951,316 bp[1]
End9,995,694 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

160364

232413

Ensembl

ENSG00000172322

ENSMUSG00000053063

UniProt

Q5QGZ9

Q504P2

RefSeq (mRNA)

NM_001207010
NM_001300730
NM_138337
NM_201623
NM_201625

NM_177686

RefSeq (protein)

NP_001193939
NP_001287659
NP_612210
NP_963917

NP_808354

Location (UCSC)Chr 12: 9.95 – 10 MbChr 6: 129.34 – 129.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

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.[6][7]

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.[6]

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.[8]

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.[9][10]

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.[11]

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.[12][13]

References
  1. GRCh38: Ensembl release 89: ENSG00000172322 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000053063 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: CLEC12A C-type lectin domain family 12, member A".
  6. Marshall AS, Willment JA, Pyz E, Dennehy KM, Reid DM, Dri P, et al. (August 2006). "Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation". European Journal of Immunology. 36 (8): 2159–69. doi:10.1002/eji.200535628. PMID 16838277.
  7. Marshall AS, Willment JA, Lin HH, Williams DL, Gordon S, Brown GD (April 2004). "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. doi:10.1074/jbc.m313127200. PMID 14739280.
  8. Pyz E, Huysamen C, Marshall AS, Gordon S, Taylor PR, Brown GD (April 2008). "Characterisation of murine MICL (CLEC12A) and evidence for an endogenous ligand". European Journal of Immunology. 38 (4): 1157–63. doi:10.1002/eji.200738057. PMC 2430328. PMID 18350551.
  9. Yoshida GJ, Saya H (January 2016). "Therapeutic strategies targeting cancer stem cells". Cancer Science. 107 (1): 5–11. doi:10.1111/cas.12817. PMC 4724810. PMID 26362755.
  10. Zhou J, Chng WJ (September 2014). "Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia". World Journal of Stem Cells. 6 (4): 473–84. doi:10.4252/wjsc.v6.i4.473. PMC 4172676. PMID 25258669.
  11. Leong SR, Sukumaran S, Hristopoulos M, Totpal K, Stainton S, Lu E, et al. (February 2017). "An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia". Blood. 129 (5): 609–618. doi:10.1182/blood-2016-08-735365. PMC 5290988. PMID 27908880.
  12. Laborda E, Mazagova M, Shao S, Wang X, Quirino H, Woods AK, et al. (October 2017). "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. doi:10.3390/ijms18112259. PMC 5713229. PMID 29077054.
  13. Tashiro H, Sauer T, Shum T, Parikh K, Mamonkin M, Omer B, et al. (September 2017). "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. doi:10.1016/j.ymthe.2017.05.024. PMC 5589064. PMID 28676343.

Further reading
  • Drickamer K (October 1999). "C-type lectin-like domains". Current Opinion in Structural Biology. 9 (5): 585–90. doi:10.1016/S0959-440X(99)00009-3. PMID 10508765.
  • van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. (October 2007). "The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells". Blood. 110 (7): 2659–66. doi:10.1182/blood-2007-03-083048. PMID 17609428.
  • Marshall AS, Willment JA, Pyz E, Dennehy KM, Reid DM, Dri P, et al. (August 2006). "Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation". European Journal of Immunology. 36 (8): 2159–69. doi:10.1002/eji.200535628. PMID 16838277.
  • Chen CH, Floyd H, Olson NE, Magaletti D, Li C, Draves K, Clark EA (February 2006). "Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production". Blood. 107 (4): 1459–67. doi:10.1182/blood-2005-08-3264. PMC 1895401. PMID 16239426.
  • Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA, et al. (November 2004). "C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia". Cancer Research. 64 (22): 8443–50. doi:10.1158/0008-5472.CAN-04-1659. PMID 15548716.
  • Han Y, Zhang M, Li N, Chen T, Zhang Y, Wan T, Cao X (November 2004). "KLRL1, a novel killer cell lectinlike receptor, inhibits natural killer cell cytotoxicity". Blood. 104 (9): 2858–66. doi:10.1182/blood-2004-03-0878. PMID 15238421.
  • Marshall AS, Willment JA, Lin HH, Williams DL, Gordon S, Brown GD (April 2004). "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. doi:10.1074/jbc.M313127200. PMID 14739280.
  • Ebner S, Sharon N, Ben-Tal N (October 2003). "Evolutionary analysis reveals collective properties and specificity in the C-type lectin and lectin-like domain superfamily". Proteins. 53 (1): 44–55. doi:10.1002/prot.10440. PMID 12945048.
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