MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

2014-09-01 Carolina Vicente-Dueñas , Ines González-Herrero , Idoia García-Ramírez , Isidro Sánchez-García Affiliation

Identity

HGNC

MAFB

LOCATION

20q12

LOCUSID

9935

ALIAS

DURS3,KRML,MCTO

FUSION GENES

Show Gene Fusions

Abstract

The MAFB protein is a basic leucine zipper (bZIP) transcription factor that plays important roles both in development and in the regulation of lineage-specific hematopoiesis. This gene contains no introns. The abnormal function of MAFB has been implicated in multiple myeloma, myeloid leukemias, multicentric carpotarsal osteolysis, Dupuytrens disease and nonsyndromic cleft lip.

DNA/RNA

Note

The MAFB open reading frame is encoded by a unique exon.

Description

MAFB gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 kb (Cordes and Barsh, 1994; Sieweke et al., 1996).

Transcription

1 exon, 3378 bp.
Ubiquitous expression of MAFB.

Proteins

Note

MAF family members, such as MAFB, are basic region/leucine zipper transcription factors that affect transcription positively or negatively, depending on their partner proteins and the context of the target promoter (Wang et al., 1999).

Protein structure of MAFB.

Description

Sequence length: 323 aa.
Molecular mass of 35792 Da.
Sequence similarities: MAFB belongs to the bZIP family. MAF family contains one bZIP (basic-leucine zipper) domain.

Expression

MAFB is expressed in the digestive, endocrine and in immature myeloid/monocytic cells but not in lymphocytes.

Localisation

Intracellular, nucleus.

Function

Transcription factor; DNA binding protein.
MAFB acts as a transcriptional activator or repressor. It plays a role in erythroid differentiation and in the haematopoietic system it is expressed in immature myeloid/monocytic cells but not in lymphocytes (Kelly et al., 2000). MAFB plays a pivotal role in regulating lineage-specific hematopoiesis by repressing ETS1-mediated transcription of erythroid-specific genes in myeloid cells (Zanocco-Marani et al., 2009). It is also required for monocytic, macrophage, podocyte and islet beta cell differentiation (Kelly et al., 2000; Sevinsky et al., 2004; Bakri et al., 2005; Gemelli et al., 2008; Vanhoose et al., 2008; Aziz et al., 2009). SUMO modification controls its transcriptional activity and ability to specify macrophage fate (Tillmanns et al., 2007). Together with MAFA, MAFB regulates PDX1 transcription in pancreatic beta cells (Vanhoose et al., 2008). It is also involved in renal tubule survival and F4/80 maturation (Moriguchi et al., 2006). This protein activates the insulin and glucagon promoters. Together with PAX6, MAFB transactivates weakly the glucagon gene promoter through the G1 element (Gosmain et al., 2010). MAFB induces osteoclastogenesis and is essential for normal renal development (Zankl et al., 2012). It is a regulator of hindbrain segmentation and interacts with the ICD of LRP1 through a leucine zipper domain (Petersen et al., 2004). It is involved either as an oncogene or as a tumor suppressor, depending on the cell context, in multiple myeloma and myeloid leukemia development (Eychène et al., 2008).
It is implicated in the following physiological biological processes: rhombomere 6 development; segment specification; negative regulation of erythrocyte differentiation; inner ear morphogenesis; sensory organ development; transcription, DNA-dependent; thymus development; T cell differentiation in the thymus; positive regulation of transcription from RNA polymerase II promoter; respiratory gaseous exchange; rhombomere 5 development; brain segmentation.

Homology

MAFB shares 84% amino acid identity with its murine homolog.

Implicated in

Entity name

Multiple myeloma

Disease

Multiple myeloma, also known as plasma cell myeloma, is a cancer of plasma cells. In multiple myeloma, collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells. Most cases of multiple myeloma also feature the production of a paraprotein - an abnormal antibody which can cause kidney problems. Bone lesions and hypercalcemia (high blood calcium levels) are also often encountered. MAFB is a specific marker for the prognostic unfavorable t(14;20)(q32;q12) in multiple myeloma patients (Stralen et al., 2009).

Prognosis

With high-dose therapy followed by autologous stem cell transplantation, the median survival has been estimated to be approximately 4.5 years in 2013, compared to a median of approximately 3.5 years with "standard" therapy (Child et al., 2003). Overall the 5-year survival rate is around 35% (Seiter et al., 2013).

Cytogenetics

Translocation t(14;20)(q32;q12).

Hybrid gene

IGH-MAFB given rise to and aberrant expression of MAFB.

Translocation t(14;20) is implicated in multiple myeloma. Chromosomal translocations of the immunoglobulin heavy chain (IgH) gene region at 14q32 are regularly involved in B lymphoid malignancies. The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB.

Fusion protein

No fusion protein. Only aberrant expression of MAFB.

Oncogenesis

Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of MAF oncogenes (associated to human plasma cell neoplasias) are targeted to mouse B cells, the resulting animals fail to reproduce the human disease. An engineered transgenic mice that express MafB in haematopoietic stem/progenitor cells (HS/PCs) reproduced human multiple myeloma disease suggesting that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias (Vicente-Dueñas et al., 2012b). And the loss of p53 exacerbates this tumor stem cell reprogramming process (Vicente-Dueñas et al., 2012a).

Entity name

Myeloid leukemia

Note

MAFB gene is deleted in myeloid leukemias (Wang et al., 1999). A deletion of the long arm of chromosome 20 [del(20q)] is a recurring abnormality in a wide spectrum of myeloid disorders. Loss of genetic material from 20q seems to confer a proliferative advantage to myeloid cells, possibly through loss of function of a tumor suppressor gene (Wang et al., 1998).

Disease

Myeloid leukemia is a type of leukemia affecting myeloid tissue. There are two main types, acute myeloid leukemia and chronic myelogenous leukemia.

Cytogenetics

Deletion of the long arm of chromosome 20.

Entity name

Multicentric carpotarsal osteolysis (MCTO)

Note

Multicentric carpotarsal osteolysis is due to a heterozygosity missense mutations in the MAFB gene. The mutations were clustered within a 51-bp region of the single exon of MAFB at the N-terminal transcription activation domain. The allelic variants are: THR62PRO; SER70ALA; SER70LEU; PRO71SER; PRO71LEU and PRO54LEU (Zankl et al., 2012).

Disease

Defects in MAFB are the cause of multicentric carpotarsal osteolysis syndrome (MCTO). MCTO is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved.
Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. The main clinical features are progressive destruction of the carpal and tarsal bone and other bones may also be involved, associated with chronic renal failure, mental retardation and minor facial anomalies.

Entity name

Dupuytrens disease (DD)

Note

Microarray analysis identified significantly upregulatation of MAFB among other genes in Dupuytrens disease. MAFB immunohistochemistry showed positive staining in 50% of the DD specimens studied (Lee et al., 2006).

Disease

Dupuytrens disease is characterized by fibroblastic proliferation of the palmar fascia, often leading to flexion contracture in the hand, where the fingers bend towards the palm and cannot be fully extended (Lee et al., 2006). Dupuytrens contracture progresses slowly and is often accompanied by some aching and itching. In patients with this condition, the palmar fascia thickens and shortens so that the tendons connected to the fingers cannot move freely. Incidence increases after the age of 40.

Entity name

Nonsyndromic cleft lip (NSCLP)

Note

Nonsyndromic cleft lip with or without cleft palate is a common isolated orofacial birth defect. The etiology of NSCLP is complex with both genetic and environmental factors implicated, but to date approximately only 20% of the genetic susceptibility has been identified (Vieira, 2008). Genome-wide association studies support for the association of MAFB and NSCLP (Yuan et al., 2011).

Disease

Cleft lip is a type of clefting congenital deformity caused by abnormal facial development during gestation. It is the non-fusion of the bodys natural structures that form before birth. A cleft lip or palate can be successfully treated with surgery, especially so if conducted soon after birth or in early childhood.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19892988	2009	MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages.	Aziz A et al
15598817	2005	Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate.	Bakri Y et al
12736280	2003	High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.	Child JA et al
8001130	1994	The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor.	Cordes SP et al
19143053	2008	A new MAFia in cancer.	Eychène A et al
18832725	2008	The vitamin D3/Hox-A10 pathway supports MafB function during the monocyte differentiation of human CD34+ hemopoietic progenitors.	Gemelli C et al
20592023	2010	Pax6 controls the expression of critical genes involved in pancreatic {alpha} cell differentiation and function.	Gosmain Y et al
10790365	2000	MafB is an inducer of monocytic differentiation.	Kelly LM et al
16473681	2006	Expression of a novel gene, MafB, in Dupuytren's disease.	Lee LC et al
16847325	2006	MafB is essential for renal development and F4/80 expression in macrophages.	Moriguchi T et al
15135046	2004	Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development.	Petersen HH et al
15121870	2004	Extracellular signal-regulated kinase induces the megakaryocyte GPIIb/CD41 gene through MafB/Kreisler.	Sevinsky JR et al
8620536	1996	MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation.	Sieweke MH et al
18830254	2009	MafB oncoprotein detected by immunohistochemistry as a highly sensitive and specific marker for the prognostic unfavorable t(14;20) (q32;q12) in multiple myeloma patients.	Stralen E et al
17548468	2007	SUMO modification regulates MafB-driven macrophage differentiation by enabling Myb-dependent transcriptional repression.	Tillmanns S et al
18522939	2008	MafA and MafB regulate Pdx1 transcription through the Area II control region in pancreatic beta cells.	Vanhoose AM et al
22903061	2012	A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors.	Vicente-Dueñas C et al
18218836	2008	Unraveling human cleft lip and palate research.	Vieira AR et al
10444328	1999	Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias.	Wang PW et al
9491317	1998	Refinement of the commonly deleted segment in myeloid leukemias with a del(20q).	Wang PW et al
21567910	2011	Association of ABCA4 and MAFB with non-syndromic cleft lip with or without cleft palate.	Yuan Q et al
22387013	2012	Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB.	Zankl A et al
19332055	2009	TFE3 transcription factor regulates the expression of MAFB during macrophage differentiation.	Zanocco-Marani T et al

Other Information

Locus ID:

NCBI: 9935
MIM: 608968
HGNC: 6408
Ensembl: ENSG00000204103

Variants:

dbSNP: 9935
ClinVar: 9935
TCGA: ENSG00000204103
COSMIC: MAFB

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000204103	ENST00000373313	Q9Y5Q3

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Developmental Biology	REACTOME	R-HSA-1266738
Activation of HOX genes during differentiation	REACTOME	R-HSA-5619507
Activation of anterior HOX genes in hindbrain development during early embryogenesis	REACTOME	R-HSA-5617472

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA164713366	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Chemical	ClinicalAnnotation	associated	PD
PA283	MAPK8	Gene	Pathway	associated		23922006
PA30621	MAPK14	Gene	Pathway	associated		23922006
PA443434	Arthritis, Rheumatoid	Disease	ClinicalAnnotation	associated	PD

References

Pubmed ID	Year	Title	Citations
35249929	2023	Podocyte-specific Transcription Factors: Could MafB Become a Therapeutic Target for Kidney Disease?	0
36764337	2023	Misexpression of LINC01410, FOSL1, and MAFB in peripheral blood mononuclear cells associated with diabetic nephropathy.	0
36897571	2023	MafB-dependent neurotransmitter signaling promotes β cell migration in the developing pancreas.	2
36930354	2023	Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB.	4
37917179	2023	MAFB shapes human monocyte-derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression.	0
37996430	2023	Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.	0
35249929	2023	Podocyte-specific Transcription Factors: Could MafB Become a Therapeutic Target for Kidney Disease?	0
36764337	2023	Misexpression of LINC01410, FOSL1, and MAFB in peripheral blood mononuclear cells associated with diabetic nephropathy.	0
36897571	2023	MafB-dependent neurotransmitter signaling promotes β cell migration in the developing pancreas.	2
36930354	2023	Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB.	4
37917179	2023	MAFB shapes human monocyte-derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression.	0
37996430	2023	Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.	0
34893889	2022	Coordinated glucocorticoid receptor and MAFB action induces tolerogenesis and epigenome remodeling in dendritic cells.	14
34904217	2022	GPBAR1 promotes proliferation and is related to poor prognosis of high-grade glioma via inducing MAFB expression.	0
34964110	2022	Duane retraction syndrome characterized by inner ear agenesis and neurodevelopmental phenotype in an Italian family with a variant in MAFB.	0

Citation

Carolina Vicente-Dueñas ; Ines González-Herrero ; Idoia García-Ramírez ; Isidro Sánchez-García

MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/41236/mafb-(v-maf-avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-b)