ALDH Enzymes and Hematological Diseases: A Scoping Review of Literature

Aldehyde dehydrogenases (ALDHs) constitute a group of enzymes that catalyze the oxidation of aldehydes to carboxylic acids. The human ALDH superfamily, including 19 different isoenzymes (ALDH1A1, ALDH1A2, ALDH1A3, AHDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDHA16A1, ALDH18A1), displays different key physiological and toxicological functions, with specific tissue expression and substrate specificity. Several studies have established that ALDH are interesting markers for the identification and quantification of human hematopoietic stem cells and cancer stem cells, notably leukemic stem cells. ALDH2 is the best-documented enzyme, in this family, as having an impact on hematology, particularly myeloid malignancies. ALDH2 mainly catalyzes the detoxification of toxic aldehydes (acetaldehyde, formaldehyde). For example, ALDH2 detoxifies formaldehyde, which is produced during the differentiation of hematopoietic progenitors. The trigger of alcohol dehydrogenase 5 (also known as formaldehyde dehydrogenase or S-nitrosoglutathione reductase, ADH5/FDH/GSNOR)/ALDH2 allows to eliminate formaldehyde and ensures normal hematopoiesis. Moreover, the ALDH2*2 variant allele is the most frequent ALDH2 variant, found in 35-45% of individuals of East Asian origin. It is associated with altered acetaldehyde metabolism and is involved in several hematological diseases (aplastic anemia, bone marrow failure, myelodysplastic syndrome). This review presents current knowledge of different members of the ALDH family and their involvement in normal and malignant hematopoiesis. Focus was brought to the ALDH2 isoenzyme in congenital (Fanconi anemia, Aplastic anemia, mental retardation, and dwarfism (AMeD) syndrome, and idiopathic aplastic anemia) and acquired (acute myeloid leukemia and myelodysplastic syndrome) hematological diseases. It also describes the possibilities of using ALDH as both a biomarker and therapeutic target, to identify and eradicate leukemic stem cells in malignant diseases.