ALDH1A2 explained

Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.^{[1] [2]}

Function

ALDH1a2 belongs to the aldehyde dehydrogenase family of proteins, and specifically the ALDH1 family. The product of this gene, ALDH1a2, is an enzyme that catalyzes the synthesis of all-trans retinoic acid (RA) from retinaldehyde in a NAD-dependent manner.^[3] Retinoic acid, the active derivative of vitamin A (retinol), is a retinoid nuclear receptor ligand that functions in developing and adult tissues.^[4]

ALDH1a2 is critical to fetal development by activating the RAR nuclear receptors. Studies of ALDH1a2 in mice suggest that this enzyme and the cytochrome CYP26A1 enzyme coordinate local embryonic retinoic acid levels that facilitate posterior organ development and prevent spina bifida.^[5]

In adult tissues, ALDH1a2 is know to regulate immune tolerance in the colon and other mucosal tissues by generating retinoic acid as a paracrine signal to CD4 T cells.^[6] ALDH1a2 also works in conjunction with ALDH1a1 to establish sufficient retinoic acid levels in the testes to support spermatogenesis.^[7] Due to its role in suppressing immune cells as well as its unique amplification in T cell Acute Lymphoblastic Leukemia (T-ALL), ALDH1a2 has been suggested as a target for cancer therapy.

Clinical significance

Involvement in T-ALL

ALDH1A2 is abnormally amplified in more than half of instances of T-cell acute lymphoblastic leukemia (T-ALL).^[8] T-ALL is a leukemia that arises from immature T-cell precursors and is an aggressive form of cancer that primarily affects children but also occurs in adults. T-ALL is caused when one or more genes encoding transcription factors including TAL1, TLX1, HOXA, TAL2, LYL1, LMO1, LMO2, or NKX3 are genetically fused to other chromosomal regions. ALDH1A2 is one of the recognized downstream targets of TAL1 fusion genes which works by binding to the intronic regulatory element of ALDH1a2, thereby inducing a T-ALL specific isoform with enzymatic activity.^[9] TAL-1 positive T-ALL accounts for approximately 40-60% of all primary T-ALL cases. According to researchers’ data, depletion of ALDH1A2 in T-ALL led to reduced cell viability in T-cell lines and caused apoptosis.

Involvement in solid tumors

ALDH1a2 is not expressed in most cancer cells and comparison studies reveal that it is often expressed at lower levels in tumors compared to adjacent normal tissues.^[10] This contrasts with the related family members ALDH1a1 and ALDH1a3. For instance, the ALDH1A2 promoter region is hypermethylated in primary prostate tumors compared with normal prostate specimens, resulting in lower ALDH1a2 expression in prostate cancers.^[11] In contrast to tumor cells, ALDH1a2 is expressed in many monocyte-derived populations known to reside in tumors such as alternatively activated macrophages and other antigen presenting cells.^[12] Glioblastoma-associated macrophages highly express ALDH1A2 when compared to other ALDH family enzymes and this higher expression is associated with tumor recurrence.^[13]

Population genetic studies

ALDH1a2 is key regulator of development due to its role in producing retinoic acid in the developing fetus. Key organs affected by ALDH1a2 during development include the heart and neural tube. Several small population studies have examined a link between single nucleotide polymorphisms in the ALDH1A2 gene and various disease states. In a case control study of 103 patients with congenital heart disease, ALDH1a2 SNPs were identified in patients, but the levels did not significantly differ from case controls^[14] suggesting known ALDH1a2 polymorphisms do not affect risk of congenital heart disease.

In contrast, SNPs found in ALDH1a2 introns show statistically significant associations with hand osteoarthritis.^[15] Extensive characterization of these loci show that SNPs associated with hand osteoarthritis result in quantitative reductions of ALDH1a2 expression, suggesting that ALDH1a2 protects against synovial inflammation.  

Further reading

• Wang X, Penzes P, Napoli JL . Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli. Recognition of retinal as substrate . The Journal of Biological Chemistry . 271 . 27 . 16288–16293 . July 1996 . 8663198 . 10.1074/jbc.271.27.16288 . free .
• Zhao D, McCaffery P, Ivins KJ, Neve RL, Hogan P, Chin WW, Dräger UC . Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase . European Journal of Biochemistry . 240 . 1 . 15–22 . August 1996 . 8797830 . 10.1111/j.1432-1033.1996.0015h.x .
• Niederreither K, Subbarayan V, Dollé P, Chambon P . Embryonic retinoic acid synthesis is essential for early mouse post-implantation development . Nature Genetics . 21 . 4 . 444–448 . April 1999 . 10192400 . 10.1038/7788 . 35572750 .
• Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dollé P . Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development . Nature Genetics . 31 . 1 . 84–88 . May 2002 . 11953746 . 10.1038/ng876 . 13607364 .
• Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A . The human plasma proteome: a nonredundant list developed by combination of four separate sources . Molecular & Cellular Proteomics . 3 . 4 . 311–326 . April 2004 . 14718574 . 10.1074/mcp.M300127-MCP200 . free .
• Deak KL, Dickerson ME, Linney E, Enterline DS, George TM, Melvin EC, Graham FL, Siegel DG, Hammock P, Mehltretter L, Bassuk AG, Kessler JA, Gilbert JR, Speer MC . Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2 . Birth Defects Research. Part A, Clinical and Molecular Teratology . 73 . 11 . 868–875 . November 2005 . 16237707 . 10.1002/bdra.20183 . free .
• Ribes V, Wang Z, Dollé P, Niederreither K . Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling . Development . 133 . 2 . 351–361 . January 2006 . 16368932 . 10.1242/dev.02204 . free .

Notes and References

1. Ono Y, Fukuhara N, Yoshie O . TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3 . Molecular and Cellular Biology . 18 . 12 . 6939–6950 . December 1998 . 9819382 . 109277 . 10.1128/MCB.18.12.6939 .
2. Web site: Entrez Gene: ALDH1A2 aldehyde dehydrogenase 1 family, member A2.
3. Mic FA, Molotkov A, Benbrook DM, Duester G . Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis . Proceedings of the National Academy of Sciences of the United States of America . 100 . 12 . 7135–7140 . June 2003 . 12782789 . 165842 . 10.1073/pnas.1231422100 . free . 2003PNAS..100.7135M .
4. Duester G . Retinoic acid synthesis and signaling during early organogenesis . Cell . 134 . 6 . 921–931 . September 2008 . 18805086 . 2632951 . 10.1016/j.cell.2008.09.002 .
5. Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dollé P . Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development . Nature Genetics . 31 . 1 . 84–88 . May 2002 . 11953746 . 10.1038/ng876 .
6. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H . Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid . Science . 317 . 5835 . 256–260 . July 2007 . 17569825 . 10.1126/science.1145697 .
7. Topping T, Griswold MD . Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis . Frontiers in Endocrinology . 13 . 871225 . 2022 . 35574006 . 9097449 . 10.3389/fendo.2022.871225 . free .
8. Zhang C, Amanda S, Wang C, King Tan T, Zulfaqar Ali M, Zhong Leong W, Moy Ng L, Kitajima S, Li Z, Eng Juh Yeoh A, Hao Tan S, Sanda T . Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia . Haematologica . 106 . 6 . 1545–1558 . June 2021 . 32414855 . 8168519 . 10.3324/haematol.2019.245639 .
9. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, McCastlain K, Edmonson M, Pounds SB, Shi L, Zhou X, Ma X, Sioson E, Li Y, Rusch M, Gupta P, Pei D, Cheng C, Smith MA, Auvil JG, Gerhard DS, Relling MV, Winick NJ, Carroll AJ, Heerema NA, Raetz E, Devidas M, Willman CL, Harvey RC, Carroll WL, Dunsmore KP, Winter SS, Wood BL, Sorrentino BP, Downing JR, Loh ML, Hunger SP, Zhang J, Mullighan CG . The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia . Nature Genetics . 49 . 8 . 1211–1218 . August 2017 . 28671688 . 5535770 . 10.1038/ng.3909 .
10. Web site: Expression of ALDH1A2 in cancer - Summary - The Human Protein Atlas . 2024-12-03 . www.proteinatlas.org.
11. Kim H, Lapointe J, Kaygusuz G, Ong DE, Li C, van de Rijn M, Brooks JD, Pollack JR . The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer . Cancer Research . 65 . 18 . 8118–8124 . September 2005 . 16166285 . 10.1158/0008-5472.CAN-04-4562 .
12. Yokota-Nakatsuma A, Ohoka Y, Takeuchi H, Song SY, Iwata M . Beta 1-integrin ligation and TLR ligation enhance GM-CSF-induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties . Scientific Reports . 6 . 1 . 37914 . November 2016 . 27897208 . 5126582 . 10.1038/srep37914 . 2016NatSR...637914Y .
13. Kim H, Lapointe J, Kaygusuz G, Ong DE, Li C, van de Rijn M, Brooks JD, Pollack JR . The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer . Cancer Research . 65 . 18 . 8118–8124 . September 2005 . 16166285 . 10.1158/0008-5472.CAN-04-4562 .
14. Pavan M, Ruiz VF, Silva FA, Sobreira TJ, Cravo RM, Vasconcelos M, Marques LP, Mesquita SM, Krieger JE, Lopes AA, Oliveira PS, Pereira AC, Xavier-Neto J . ALDH1A2 (RALDH2) genetic variation in human congenital heart disease . BMC Medical Genetics . 10 . 113 . November 2009 . 19886994 . 2779186 . 10.1186/1471-2350-10-113 . free .
15. Shepherd C, Zhu D, Skelton AJ, Combe J, Threadgold H, Zhu L, Vincent TL, Stuart P, Reynard LN, Loughlin J . Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant . Arthritis & Rheumatology . 70 . 10 . 1577–1587 . October 2018 . 29732726 . 6175168 . 10.1002/art.40545 .