CRLF2 gene is located in reverse strand of pseudo-autosomal region 1 (PAR1) in X and Y chromosomes. CRLF2 encompasses 22kb of DNA and give rise to four transcript variants with different lengths: 1.6, 1.5, 1.0 and 1.7 kb. ENSG00000205755

CRLF2 gene encodes a member of type I cytokine receptor family and generate four transcript variants (Table 1). Three generate protein coding transcripts and one generates a non-sense mediated decay transcript.
According with gene expression array data CRLF2 is expressed, from highest to lowest, in: cervix > lung > bladder > small intestine > esophagus > stomach > skin > prostate > uterus > vagina > testes > colon > spleen > mammary gland > thyroid > whole blood.
It has been reported that in pathological conditions the transcription rate of CRLF2 is altered. CRLF2 overexpression (fold change > 2) is found in: microbial infection, immunodeficiency syndromes (X-linked hyper IgM syndrome), autoimmune diseases (arthritis), and cancer (esophagus dysplasia, papillary thyroid carcinoma and acute lymphoblastic leukemia). The CRLF2 subexpression (fold change < 2) has been reported only in cancer (myelodysplastic syndrome, non-small cell lung carcinoma, hepatobiliary carcinoma, colorectal carcinoma, pancreatic adenocarcinoma and breast carcinoma). ENSG00000205755; UniProt Q9HC73; neXtProt NX_Q9HC73
Table 1. Transcript variants and proteins

Name (RefSeq)	Exons	Coding Exons	Transcript Length	Protein Length	Type of transcript
CRLF2-203 (NM_022148)	8	8	1, 639 bp	371 residues	Protein coding
CRLF2-201	9	8	1, 545 bp	371 residues	Protein coding
CRLF2-202 (NM_001012288)	7	6	1, 013 bp	259 residues	Protein coding
CRLF2-204 (NR_110830)	8	5	1, 789 bp	232 residues	Non-sense mediated decay

CRLF2 gene encodes a member of the type I cytokine receptor family. CRLF2 has three protein coding transcripts: CRLF2-201, CRLF2-202, CRLF2-203 and CRLF2-204.
CRLF2-203 and CRLF2-201 transcript variants generate the longer isoform of 371 amino acids (42 kDa), also called isoform 1.
Isoform 1 has the protein regions that characterize this family gene: FN3 (Fibronectin type 3) region, WSXWS motif, Box 1 motif, and transmembrane region. Post-translational modifications of CRLF2 protein include glycosylation at asparagine residues (Asn169, Asn55 and Asn47) and phosphorylation at isoleucine (Ile271) and tyrosine (Tyr74) residues.
The other isoform, called isoform 2, is encoded by the transcript variant CRLF2-202. This isoform is shorter, 259 amino acids (26.6 kDa), at N-terminus compared with isoform 1 because lacks an alternate exon which results in translation initiation at a downstream start codon. ENSG00000205755; UniProt Q9HC73, Q9HC73-2, Q4V300; neXtProt NX_Q9HC73

CRLF2 protein is present in intestine, bone marrow, spleen, thymus, and is more abundant in dendritic cells. neXtProt NX_Q9HC73

CRLF2 isoform 1 is a cell membrane protein and CRLF2 isoform 2 is a secreted protein.

CRLF2 forms a functional complex with IL-7Rα (IL-7 receptor α chain) and TSLP (thymic stromal lymphopoietin). Functional complex activation induces different signals depending on the type of cell and also exerts multiple functions. Heterocomplex is involved in a plethora of physiologic and pathologic immune functions, including: tolerance, allergy, autoimmune diseases and cancer. (Tsilingin et al., 2017).
CRLF2 is expressed mainly in dendritic cells and also hematopoietic cells including T cells, B cells, granulocytes, and mast cells. Heterocomplex main function is the differentiation to T helper type 2 (Th2) cells. CRLF2-activated dendritic cells express OX40 ligand and trigger naive CD4⁺ to differentiate into inflammatory Th2 cells and the expansion of allergen-specific Th2 memory cells (Lin et al., 2018).
According with phosphoproteome analysis in diverse cell types, after TSLP binds to the CRLF2/IL-7Rα heterocomplex, the phosphorylation of Janus kinase1 ( JAK1) and 2 ( JAK2) activates signal transducers and activators of transcription (STATs) proteins, including: STAT1, STAT3, STAT4, STAT5A, STAT5B and STAT6. Heterocomplex also activates other signaling molecules such as PI3K/AKT/MTOR pathway, SRC / TEC pathway, MAPK3 / MAPK1 (ERK1/2), NF-kB, MAPK8 / MAPK9 (JNK1 JNK2), and p38/MAPK activation (Zhong Jun et al., 2012; Zhong Jun et al., 2014).
In allergy or autoimmune disease has been described high expression of TSLP and overstimulation of TSLP/CRLF2/IL-7Rα complex. Tezepelumab is a human monoclonal antibody that blocks functional complex and is successfully used in asthma treatment (Van Rompaey et al., 2012).
The role of functional heterocomplex in cancer is still controversial, in certain neoplasia plays a pro-tumorigenic role, whereas in others, a protective role. For example, in cervix, breast, and pancreas cancer has been describe an increase of metastasis associated with an overstimulation of TSLP/CRLF2/IL-7Rα. On the other hand, in colon and skin carcinoma, functional heterocomplex has been associated with better prognostic. In addition to above, CRLF2 gene has genetic alterations that promote cell survival in cancer. The genetic rearrangements P2RY8/CRLF2 and IGH/CRLF2, generate CRLF2 overexpression, and the mutation Phe232Cys, encodes CRLF2 proteins capable of forming homodimers and self-activation, both described in acute lymphoblastic leukemia (Varricchi et al., 2018; Zhong Jun, 2014).

Table 2. CRLF2 Orthologues

Name	Organism
CRLF2	P. troglodytes
CRLF2 (ENSCAFG00000011034)	C. lupus
LOC529792 (ENSBTAG00000020242)	B. taurus
Crlf2 (ENSMUSG00000033467)	M. musculus
Crlf2 (ENSRNOG00000049828)	R. novergicus
LOC418668 (ENSGALG00000016696)	G. gallus

Table 3 CRLF2 mutations in cancer

CDS Mutation	Cancer Type	Type of Mutation
c.315C>A	Bladder Carcinoma	Missense mutation
c.357C>A	Bladder Carcinoma	Missense mutation
c.193G>A	Bladder Carcinoma	Missense mutation
c.89T>A	Bladder Carcinoma	Missense mutation
c.33C>G	Diffuse Large B Cell Lymphoma	Missense mutation
c.415T>C	Diffuse Large B Cell Lymphoma	Missense mutation
c.349C>T	Osteosarcoma	Missense mutation
c.330T>C	Colon Carcinoma	Missense mutation
c.384G>A	Colon Carcinoma	Missense mutation
c.33C>G	Colon Carcinoma	Missense mutation
c.159G>A	Rectum Carcinoma	Missense mutation
c.474C>T	Adenocarcinoma	Missense mutation
c.372C>T	Adenocarcinoma	Missense mutation
c.411G>A	Adenocarcinoma	Missense mutation
c.603C>T	Adenocarcinoma	Missense mutation
c.405G>A	Adenocarcinoma	Missense mutation
c.669G>A	Adenocarcinoma	Missense mutation
c.642T>C	Adenocarcinoma	Missense mutation
c.642T>C	Endometrioid Carcinoma	Missense mutation
c.321C>T	Lung Carcinoma	Missense mutation
c.384G>A	Pleura Carcinoma	Missense mutation
c.456C>T	Melanoma	Missense mutation
c.411G>A	Melanoma	Missense mutation
c.468C>T	Melanoma	Missense mutation
c.123C>T	Melanoma	Missense mutation
c.630G>A	Melanoma	Missense mutation
c.534G>A	Melanoma	Missense mutation
c.438C>T	Melanoma	Missense mutation
c.383C>T	Merkel Cell Carcinoma	Missense mutation
c-.335G>T	Merkel Cell Carcinoma	Missense mutation
c.604G>A	Urinary Tract Carcinoma	Missense mutation
c.742C>A	Urinary Tract Carcinoma	Missense mutation
c.208C>A	Neuroblastoma	Missense mutation
c.139A>T	Glioma	Missense mutation
c.404C>T	Glioma	Missense mutation
c.365C>T	Glioma	Missense mutation
c.598C>A	Glioma	Missense mutation
c.404C>T	Glioma	Missense mutation
c.313C>T	Glioma	Missense mutation
c.74G>A	Glioma	Missense mutation
c.632G>A	Glioma	Missense mutation
c.445G>A	Meningioma	Missense mutation
c.660G>T	Breast Carcinoma	Missense mutation
c.734C>T	Breast Carcinoma	Missense mutation
c.526G>C	Breast Carcinoma	Missense mutation
c.297C>G	Cervix Carcinoma	Missense mutation
c.658G>C	Cervix Carcinoma	Missense mutation
c.566C>T	Endometrium Carcinoma	Missense mutation
c.536A>T	Endometrium Carcinoma	Missense mutation
c.643C>T	Endometrium Carcinoma	Missense mutation
c.7C>T	Endometrium Carcinoma	Missense mutation
c.496A>C	Endometrium Carcinoma	Missense mutation
c.373G>A	Endometrium Carcinoma	Missense mutation
c.346T>C	Endometrium Carcinoma	Missense mutation
c.495A>C	Endometrium Carcinoma	Missense mutation
c.248G>T	Kidney Carcinoma	Missense mutation
c.526G>A	Liver Carcinoma	Missense mutation
c.105C>G	Liver Carcinoma	Missense mutation
c.671C>T	Acute Myeloid Leukemia	Missense mutation
c.695T>G	B Cell Acute Lymphoblastic Leukemia	Missense mutation
c.2T>A	Mantle Cell Lymphoma	Missense mutation
c.340G>C	Marginal Zone Lymphoma	Missense mutation
c.228C>T	Head and Neck Carcinoma	Missense mutation
c.764G>A	Melanoma	No sense mutation
c.764G>A	Melanoma	No sense mutation
c.755G>A	Head and Neck Carcinoma	No sense mutation
c.755G>A	Melanoma	No sense mutation
c.451C>T	Melanoma	No sense mutation
c.628C>T	Pancreas	No sense mutation
c.137G>A	Colon Carcinoma	No sense mutation
c.620C>G	Intestinal Adenocarcinoma	No sense mutation
c.91C>T	Glioblastoma Multiforme	No sense mutation
c.73G>T	Adenocarcinoma	No sense mutation
c.54G>A	Head and Neck Carcinoma	No sense mutation
c.25G>T	Lung Carcinoma	No sense mutation

Catalogue of Somatic Mutations in Cancer; cBioPortal for Cancer Genomics