View source for Acute myeloid leukemia causes

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{{Acute myeloid leukemia}}

{{CMG}}; {{AE}} {{CLG}}, {{shyam}}; {{GRR}} {{Nat}}

==Overview==
The causes of acute myeloid leukemia are broad and include [[benzene]], [[radiation]], [[Alkylating agent|alkylating]] agents, [[Type II topoisomerase|topoisomerase II]] inhibitors, and specific gene mutations. Each of these risk factors carries a defined probability of progression into acute myeloid leukemia. Acute promyelocytic leukemia is caused by a [[reciprocal translocation]] between chromosomes 15 and 17, which creates a novel protein known as ''PML-RARA'', leading to a differentiation block. Overall, most cases of acute myeloid leukemia are sporadic rather than inherited. 

==Causes==
*'''Benzene''': Benzene is a chemical liquid chemical with a sweet odor and is used in a variety of products, including heaters and other appliances. This chemical is a known cause of [[acute myeloid leukemia]].<ref name="pmid24495159">{{cite journal| author=Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D et al.| title=The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. | journal=Ann N Y Acad Sci | year= 2014 | volume= 1310 | issue=  | pages= 7-31 | pmid=24495159 | doi=10.1111/nyas.12362 | pmc=4002179 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24495159  }} </ref> In general, benzene exposure accounts for a very small fraction of acute promyelocytic leukemia, since most cases are sporadic.
*'''Radiation''': Ionizing radiation is known cause of acute [[leukemia]] of myeloid origin. Radiation-inducing DNA damage can create double-stranded breaks, which can result in leukemia.<ref name="pmid24495159">{{cite journal| author=Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D et al.| title=The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. | journal=Ann N Y Acad Sci | year= 2014 | volume= 1310 | issue=  | pages= 7-31 | pmid=24495159 | doi=10.1111/nyas.12362 | pmc=4002179 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24495159  }} </ref> In general, ionizing radiation accounts for a very small fraction of acute promyelocytic leukemia, since most cases are sporadic. If the double-stranded breaks are not properly repaired, cellular transformation can result.
*'''Alkylating agents''': Chemotherapy agents that function via DNA alkylation are known to contribute to [[acute myeloid leukemia]]. Alkylating agents include nitrogen mustards (such as carmustine ([[Carmustine (patient information)|BCNU]]) and lomustine ([[Lomustine (patient information)|CCNU]])) and [[cyclophosphamide]]. Alkylating agents typically cause late-onset leukemia: the latency between the exposure to the alkylating agent and the diagnosis of leukemia is usually 5-7 years. There is frequently an antecedent myelodysplastic phase (a precursor state of acute leukemia).
*'''Topoisomerase II inhibitors''': Chemotherapy agents that function via inhibition of topoisomerase II are known to contribute to [[acute myeloid leukemia]]. Topoisomerase II inhibitors include [[Anthracycline|anthracyclines]], [[etoposide]] (VP-16), and [[topotecan]]. Topoisomerase II inhibitors typically cause early-onset leukemia: the latency between the exposure to the topoisomerase II inhibitor and the diagnosis of leukemia is usually 2-3 years. These are usually associated with the ''MLL'' rearrangement on chromosome 11q23.
*'''Specific gene mutations''': In rare cases, acute [[leukemia]] can arise in the setting of mutations. Most of these mutations are located in genes involved in [[Epigenetics|epigenetic]] regulation. Such genes include ''TET2'', ''DNMT3A'', ''ASXL1'', and ''EZH2''. In addition to these, mutations in metabolic enzymes, such as ''IDH2'' can contribute. These mutations are more common in [[acute myeloid leukemia]] compared to [[acute promyelocytic leukemia]]. Mutations can also occur in RNA splicing genes.
**''TET2'': ''Ten eleven translocation 2'' (''TET2'') is a gene that encodes an enzyme that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The function of the TET2 protein is to effectively demethylate DNA. Mutations in this gene result confer a worse prognosis for [[acute myeloid leukemia]].<ref name="pmid24495159">{{cite journal| author=Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D et al.| title=The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. | journal=Ann N Y Acad Sci | year= 2014 | volume= 1310 | issue=  | pages= 7-31 | pmid=24495159 | doi=10.1111/nyas.12362 | pmc=4002179 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24495159  }} </ref> In general, ''TET2'' mutations occur early during leukemogenesis.
**''DNMT3A'': ''DNA methyltransferase 3a'' (''DNMT3A'') is a gene that encodes an enzyme that methylates DNA. In general, ''DNMT3A'' mutations occur early during leukemogenesis.<ref name="pmid24495159">{{cite journal| author=Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D et al.| title=The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. | journal=Ann N Y Acad Sci | year= 2014 | volume= 1310 | issue=  | pages= 7-31 | pmid=24495159 | doi=10.1111/nyas.12362 | pmc=4002179 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24495159  }} </ref>
**''[[ASXL1]]'': ''Additional sex combs like 1'' (''ASXL1'') is a transcription regulator and a modulator of histone methylation. Mutations in this gene are associated with a very poor prognosis in [[acute myeloid leukemia]].
**''[[EZH2]]'': ''Enhancer of zeste'' (''EZH2'') is a gene involved in the maintenance of transcription repression. It encodes a subunit of a histone [[methyltransferase]].<ref name="pmid24495159">{{cite journal| author=Greim H, Kaden DA, Larson RA, Palermo CM, Rice JM, Ross D et al.| title=The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. | journal=Ann N Y Acad Sci | year= 2014 | volume= 1310 | issue=  | pages= 7-31 | pmid=24495159 | doi=10.1111/nyas.12362 | pmc=4002179 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24495159  }} </ref>
**''SRSF2'': ''Serine and arginine rich splicing factor 2'' (''SRSF2'') is a gene that encodes a splicosome component. Mutations in this gene are also involved in [[myelodysplastic syndrome]].
**''[[SF3B1]]'': ''Splicing factor 3b subunit 1'' (''SF3B1'') is a gene that encodes for a splicosome component. Mutations in this gene are also involved in myelodysplastic syndrome and presence of ringed sideroblasts.
**''[[IDH2]]'': ''Isocitrate dehydrogenase 2'' (''IDH2'') is a gene that encodes for an enzyme that results in the production of 2-hydroxyglutarate, which is an oncometabolite that results in a differentiation block.<ref name="pmid29346477">{{cite journal| author=Patel SA| title=Enasidenib-Induced Differentiation Syndrome in IDH2-Mutant Acute Myeloid Leukemia. | journal=JAMA Oncol | year= 2018 | volume=  | issue=  | pages=  | pmid=29346477 | doi=10.1001/jamaoncol.2017.4724 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29346477  }} </ref> The differentiation block that arises from ''IDH2'' mutations is similar pathophysiologically to the differentiation block that occurs with the ''PML-RARA'' translocation.<ref name="pmid29346477">{{cite journal| author=Patel SA| title=Enasidenib-Induced Differentiation Syndrome in IDH2-Mutant Acute Myeloid Leukemia. | journal=JAMA Oncol | year= 2018 | volume=  | issue=  | pages=  | pmid=29346477 | doi=10.1001/jamaoncol.2017.4724 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29346477  }} </ref>


==References==
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