Population-based factors predisposing to hematopoietic neoplasia are recognized, but in most cases, the underlying mechanisms remain obscure.

Gender is an important risk factor. Females are overrepresented among neonates and infants with acute leukemia, especially leukemia with MLL rearrangement (1,2). Males predominate among all patients with acute leukemia (3).

Ethnicity appears to be a significant factor in the incidence of childhood acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and polycythemia vera (4, 5, 6, 7, 8). Some ethnic groups appear to show a higher risk of childhood leukemia, whereas others show a reduced incidence of childhood leukemia.

HLA variants have an impact on the risk of chronic myeloid leukemia (9,10).

Familial clusters of hematopoietic neoplasia have been reported (11, 12, 13, 14, 15, 16). Most kindreds show a predisposition for one type of neoplasia; some show multiple types. Familial disease may show anticipation, or progressively earlier age at onset and unusually rapid course, especially when acquired risk factors are superimposed. Familial predispostion is further discussed below.

True ethnic and familial risk factors must be distinguished from case clustering of hematologic neoplasia caused by common exposure to environmental agents, either within a geographic area or in utero.

Constitutional genetic abnormalities, mutations, and polymorphisms have often been reported in patients with hematopoietic neoplasia. They are especially relevant in therapy-induced neoplasia, in which constitutional and acquired risk factors act synergistically. Interestingly, many are identical to the acquired anomalies found in hematopoietic malignancies.

Karyotypic abnormalities associated with hematopoietic malignancies have been reported for many of the somatic chromosomes and both sex chromosomes (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29). Among
those most often reported are trisomy 21 (Down syndrome), trisomy 8, disomy Y, and abnormalities involving chromosomes 5 and 7. In such cases, the anomaly may act as an initial genetic aberration or “hit,” followed by one or more additional hits in the patient eventually diagnosed with a clonal hematopoietic disease. In other cases, it is not always clear whether the abnormality predisposes to hematopoietic disease or is merely a coincidental finding. In cases of constitutional mosaicism, hematopoietic malignancy may arise in either a karyotypically normal or abnormal cell.

Genetic mutations and polymorphisms confer an increased risk of hematopoietic malignancy, probably in combination with other factors (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50). Many of the involved genes affect drug metabolism, folate metabolism, and DNA repair. Mutations of these genes have also been discovered as acquired abnormalities in patients with leukemia. Affected genes include ATM, CEBPA, CYP1A1, CYP2E1, CYP3A4, EGFR, ERBB, ERCC1, GCNT2, GSTM1, GSTM2, GSTP1, HFE, HLX1, LIG4, MTHFR, NAT2, NF1, NQ01, NSD1, RAD51, RUNX1, TP53, TPMT, XRCC1, and others. Affected families may include individuals with ataxia-telangiectasia, familial thrombocytopenia with propensity to develop acute myelogenous leukemia, hemochromatosis, Li-Fraumeni syndrome, 3-methylglutaconic aciduria, neurofibromatosis type 1, Sotos syndrome, or other disorders.

Conversely, certain polymorphisms of CYP2D6, MDR1, RAD51, XRCC1, and other genes appear to protect against leukemia.

Constitutional hematopoietic disorders associated with an increased risk of leukemia encompass the bone marrow failure syndromes and other inherited cytopenias (51, 52, 53, 54, 55, 56). Many are further discussed in Chapter 4. These disorders include amegakaryocytic thrombocytopenia, Diamond-Blackfan anemia, dyskeratosis congenita, familial platelet disorder with acute myeloid leukemia, familial sideroblastic anemia, familial thrombocytopenia with propensity to develop acute myelogenous leukemia, Fanconi anemia, Griscelli syndrome, Kostmann syndrome, severe congenital neutropenia, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii.

Other constitutional disorders have occasionally been reported in patients with hematopoietic neoplasia (57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71). It is not clear whether the combination of a constitutional disorder and acute leukemia is etiologically significant or simply a coincidental occurrence. It is tempting to speculate that, in some cases, chronic hematopoietic stimulation brings with it an increased risk of genetic aberrations and neoplasia. These disorders include β-thalassemia, hemoglobin C, hemoglobin S, hemoglobin Lepore, hereditary spherocytosis, platelet storage pool deficiency, porphyria, pyruvate kinase deficiency, myeloperoxidase deficiency, and Fechtner syndrome.

Dysmorphic syndromes and congenital anomalies are associated with an increased incidence of hematopoietic malignancy (72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96). In such cases, the underlying connection between the dysmorphism and the malignancy is usually not known.

Specific disorders reported with hematologic neoplasia include Adams-Oliver syndrome, cardiofaciocutaneous syndrome and other cardiac anomalies, cleft lip and palate, DiGeorge syndrome, Dubowitz syndrome, Ehlers-Danlos syndrome, familial microcephaly, gonadal dysgenesis, Greig cephalopolysyndactyly, Grönblad-Strandberg syndrome, lamellar ichthyosis, Marfan syndrome, Marinesco-Sjögren syndrome, neuroectodermal dysplasia (CHIME syndrome), Noonan syndrome, Poland syndrome, Seckel syndrome, and Sipple syndrome.

Age is directly correlated with the incidence of hematopoietic neoplasia (97, 98, 99, 100, 101, 102, 103, 104, 105). Acute lymphoblastic leukemia (ALL) is prevalent in the young, and myeloproliferative neoplasms, myelodysplastic syndrome (MDS), and acute myeloblastic leukemia (AML) in older adults. ALL in the young is often acquired in utero, probably through environmental exposures transmitted through the parents. MDS and AML in the elderly resembles MDS and AML seen in patients with therapy- and toxin-induced disease, suggesting that a lifetime of environmental exposure is a major risk factor for the elderly.

Increased body weight is directly related to the risk of acute leukemia (106, 107, 108, 109, 110, 111, 112, 113, 114). In neonates, high birthweight, large-for-gestational age birthweight, and accelerated fetal growth are associated with an increased incidence of infant leukemia and acute lymphoblastic leukemia, possibly mediated by insulin-like growth factor. In adults, increased body mass index is associated with an increased risk of leukemia and particularly acute promyelocytic leukemia.

The environment contains numerous risk factors for hematologic neoplasia (115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141). These acquired factors act synergistically with constitutional risk factors to produce hematopoietic malignancy at an earlier age and higher frequency than might otherwise occur. They also influence the classification and karyotype of the hematopoietic malignancy.