Acute myeloid leukemia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Carlos A Lopez, M.D. [2], Shyam Patel [3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Overview

The causes of acute myeloid leukemia are broad and include benzene, radiation, alkylating agents, 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. 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. 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 (BCNU) and lomustine (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 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 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. 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.
  • 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.
  • 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. The differentiation block that arises from IDH2 mutations is similar pathophysiologically to the differentiation block that occurs with the PML-RARA translocation.