| Written | 2016-10 | Christine Bellanné-Chantelot, Isabelle Plo |
| Département de Génétique, Hôpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC); INSERM UMR1170, Institut Gustave Roussy, Villejuif, (CBC, IP), France. christine.bellanne-chantelot@aphp.fr; isabelle.plo@gustaveroussy.fr |
| Abstract | Autophagy is a cellular process involved in the sequestration of cytosolic components and their degradation by lysosomes. Autophagy has been involved in physiological responses to stress or aging and in the development of many human diseases including solid and haematological cancers. In humans, 16 autophagy-related genes are known. The ATG2B protein is involved in the late steps of the autophagy process i.e. the formation of autophagosomes that fuse with lysosomes before degradation. Loss-of -function (frameshift) acquired mutations of ATG2B have been identified in gastric and colorectal carcinomas with high microsatellite instability. Both pharmacologic and genetic evidence indicate that autophagy plays pleiotropic functions in hematopoietic cell homeostasis and leukemogeneis. Autophagy could exert two opposite roles (cell death and survival) depending on the nature of the hematopoietic malignancy. The germline duplication of ATG2B and GSKIP, both located in 14q32.2, predisposes to the development of familial myeloproliferative neoplasms with autosomal dominant inheritance, in particular essential thrombocythemia progressing to leukemia. Overexpression of ATG2B and GSKIP enhances megakaryocyte progenitor differentiation by increasing progenitor sensitivity to thrombopoietin. Both genes cooperate with somatic JAK2, MPL and CALR mutations and their overexpression provides a growth advantage to hematopoietic cells carrying these driver mutations that may explain the familial aggregation and the progression of essential thrombocythemia to myelofibrosis and leukemia. |
| Keywords | ATG2B; Myeloproliferative neoplasms (MPN); essential thrombocythemia; myelofibrosis; leukemia; predisposition; ATG2B/GSKIP; chromosome 14; CNV; autophagy; Wnt/beta-catenin pathway |
| Identity |
| Alias_names | C14orf103 |
| chromosome 14 open reading frame 103 | |
| ATG2 autophagy related 2 homolog B (S. cerevisiae) | |
| Alias_symbol (synonym) | FLJ10242 |
| Other alias | |
| HGNC (Hugo) | ATG2B |
| LocusID (NCBI) | 55102 |
| Atlas_Id | 55326 |
| Location | 14q32.2 [Link to chromosome band 14q32] |
| Location_base_pair | Starts at 96279202 and ends at 96363401 bp from pter ( according to hg19-Feb_2009) [Mapping ATG2B.png] |
| Local_order | telomere to centromere. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| ATG2B (14q32.2) / SLC22A17 (14q11.2) |
| Note | cooperates with GSKIP, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.96.163.103_96.857.129dup (on Assembly GRCh37) |
| DNA/RNA |
| Description | The ATG2B gene consists of 42 exons spanning a region of 82.08 kb. |
| Transcription | A single mRNA transcript (NM_018036.6) of the ATG2B gene, with a total length of 6234 nucleotides, has been annotated. |
| Pseudogene | Not yet identified. |
| Protein |
| Description | The protein encoded by the ATG2B gene is the autophagy-related protein 2 homolog B of 2078 amino acids, with a calculated molecular mass of 232.8 kDa |
| Expression | Expression of ATG2B has been detected in various normal human tissues (bone marrow, whole blood, thymus, brain, heart, muscle, colon, kidney, liver, lung, pancreas, thyroid, salivary and adrenal glands, skin, ovary, uterus, placenta, prostate and testis). In hematopoietic cells, ATG2B is expressed in CD34+ purified hematopoietic progenitors and CD36+ erythroblasts or CD41+ megakaryocytes derived from CD34+ progenitors cultured in vitro (Saliba et al, 2016) |
| Localisation | ATG2B is mainly localized in the nucleus. |
| Function | Autophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by the autophagosomes and transferred to lysosomes before degradation. The autophagy process has been extensively studied in yeast; 35 autophagy-related genes (ATG) have been identified, of which 16 are currently known in humans . This cellular process is a highly conserved among species. In humans, two ATG2 proteins, ATG2A and ATG2B, have redundant functions and are required for autophagosome formation (Velikkakath AK et al , 2012). |
| Homology | 44.5% of human ATG2B residues are identical to those of human ATG2A. |
| Mutations |
| Germinal | A germline 14q32.2 head-to-tail duplication of 700 kb has been associated with familial myeloid malignancies (Saliba et al , 2015). The germline duplication includes the genes TCL1A, GSKIP, ATG2B, BDKRB1, BDKRB2 and the first exon of AK7. The overexpression of ATG2B and GSKIP that are expressed in myeloid cells, enhances hematopoietic progenitor differentiation, particularly of megacaryocytes. The development of myeloid malignancies required the cooperation of both genes with the myeloproliferative neoplasms (MPN) driver JAK2 Val617Phe mutation, MPL or CALR mutations. The mechanism of cooperation between ATG2B and GSKIP with MPN driver mutations remains unknown. The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect. |
| Somatic | A loss-of-function somatic mutation (c.3120delA, p.Lys1040fs) in gastric carcinomas (15.6%) and in colorectal carcinomas (11.6%) (Klionsky DJ, 2009). |
| Implicated in |
| Entity | Familial myeloproliferative neoplasms (MPN) |
| Disease | Familial MPN, in particular, essential thrombocythemia progressing to myelofibrosis and/or acute myeloid leukemia and primary myelofibrosis, with autosomal dominant inheritance and originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication. The predisposition is highly penetrant (80%) and is characterized by an earlier age of MPN onset in comparison to sporadic cases (41 years versus > 60 years). The spectrum of acquired driver mutations (JAK2 Val617Phe, MPL and CALR mutations) is similar to the spectrum of mutations in sporadic MPN cases. |
| Prognosis | The percentage of transformation is close to 50% in these familial MPN cases and is related to the detection of mutations affecting epigenetic regulator genes such as TET2 IDH1 or IDH2. |
| Entity | Acute myeloid leukemia (AML) |
| Disease | AML originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication. |
| Prognosis | The prognosis of the disease is also linked to the detection of acquired mutations in TET2, IDH1 or in IDH2. No TP53 mutation was found, contrary to what was observed in AML evolving from MPN, suggesting a different pathway for leukemic transformation. |
| Entity | Gastric carcinoma |
| Note | Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of gastric carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009). |
| Entity | Colorectal cancer |
| Note | Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of colorectal carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009). |
| Bibliography |
| Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. |
| Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, Ahn CH, Yoo NJ, Lee SH |
| J Pathol; 2009;217:702-6 |
| PMID 19197948 |
| Autophagy: from phenomenology to molecular understanding in less than a decade. |
| Klionsky DJ. |
| Nat Rev Mol Cell Biol 2007;8:931-937. |
| PMID 17712358 |
| Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies |
| Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I |
| Nat Genet. 2015;47:1131-40 |
| PMID 26280900 |
| Autophagy: from phenomenology to molecular understanding in less than a decade. |
| Velikkakath AK, Nishimura T, Oita E, Ishihara N, Mizushima N. |
| Mol Biol Cell. 201;23:896-909. |
| PMID 22219374 |
| Citation |
| This paper should be referenced as such : |
| Bellanné-Chantelot C, Plo I |
| ATG2B (Autophagy-related 2B); |
| Atlas Genet Cytogenet Oncol Haematol. in press |
| On line version : http://AtlasGeneticsOncology.org/Genes/ATG2BID55326ch14q32.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
t(14;14)(q11;q32) ATG2B/SLC22A17
|
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Familial Myeloproliferative Disorders |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon May 14 12:31:52 CEST 2018 |
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