ACUTE MYELOID (MYELOGENOUS) LEUKEMIA
Whereas ALL is the most common form of acute leukemia in children, AML predominates in adults. The overall incidence of AML is 2.5 cases/100,000 per year, with the highest incidence in those over the age of 60 years. Genetic disorders which have been associated with a predisposition to AML include Down syndrome, Fanconi anemia, neurofibromatosis type 1 (NF1), and Kostmann syndrome and DNA repair defects. An autosomal dominant syndrome of cerebellar ataxia, hypoplastic anemia, and predisposition to AML (associated with monosomy 7 in bone marrow cells) has been described (Daghistani et al. 1990). Bone marrow monosomy 7 is a frequent finding in chronic myeloproliferative disorders and AML, and only a small proportion of pediatric cases will have the ataxia pancytopenia syndrome. Monosomy 7 is the most common abnormality seen in familial cases of AML, and familial clustering of AML with monosomy 7 may indeed occur (Kwong et al. 2000).
Inherited susceptibility to acute myeloid leukemia (AML) is rare apart from the conditions listed above (Horwitz et al. 1997). True nonsyndromic familial AML includes autosomal recessive disorders with myelodysplasia and monosomy 7, and some large pedigrees demonstrating autosomal dominant inheritance have been reported (Horwitz et al. 1996/1997). An autosomal dominant condition characterized by thrombocytopenia and platelet dense granule storage pool deficiency, platelet dysfunction, with a strong predisposition to acute myeloid leukemia and lymphoma, is well recognized, where the underlying genetic defect is a germline mutation in the RUNX1 (runt-related transcription factor 1) (AML1, CBFA2) gene (Dowton et al. 1985; Ganly et al. 2004). RUNX1 was first identified as the gene on chromosome 21 that is rearranged in the somatic translocation t(8:21) (q22;q22.12) detected in patients with AML. The RUNX1 protein complexes with the core-binding transcription factor (CBF) which regulates many genes involved in hematopoiesis. Other families have been described with familial AML associated with an inactivating germline CEBPA (CCAAT enhancer- binding protein) mutation, the gene encoding the granulocyte differentiating factor C/EBPα. There were latent periods of 10–30 years before the onset of overt leukemia in three affected patients in a family (Smith et al. 2004).
Homozygous or monoallelic germline inactivating mutations in EZH2 (a histone methyltransferase) have recently been found in about 12 % of a series of patients with myelodysplastic and myeloproliferative disorders (Ernst et al. 2011). Davies et al. (2003) reported an increased risk of myeloid leukemia (40-fold), but not other cancers, in individuals with Prader–Willi syndrome.
Evidence of anticipation in familial AML has been noted such that of 79 individuals in nine families transmitting the disease, the mean age at onset in the grandparental generation was 57 years, compared to 32 years in the parental generation and 13 years in the youngest generation.
A rare form of AML, erythroleukemia (FAB-M6), may be familial (Di Guglielmo syndrome) in a minority of cases. Familial erythroleukemia is a leukemic or preleukemic state in which red cell proliferation is the predominant feature. Hematologic characteristics include ineffective and hyperplastic erythropoiesis with megaloblastic components accompanied by myeloblastic proliferation of varying degree (Park et al. 2002). A possible link between a missense mutation in the erythropoietin receptor (EPOR) and erythroleukemia has been reported (Le Couedic et al. 1996), but the role of the EPOR mutation in erythroleukemia is unclear.