Insights from Familial Leukemia and Myelodysplastic Syndromes

Most malignant hematopoietic disorders arise spontaneously. Nevertheless, hereditary factors substantively contribute to risk for myelodysplastic syndrome (MDS) and leukemia, and their molecular genetic identification can help unravel pathogenesis. In some instances, germline mutations causing Mendelian forms of MDS and leukemia are similar to those occurring somatically in sporadic cases, indicating their potential to function as drivers of malignancy. In other circumstances, genes involved in hereditary predisposition to MDS and leukemia are infrequently implicated in acquired cases, suggesting they may contribute to parallel pathways of malignant transformation. Hereditary mutations in genes encoding transcription factors directing hematopoietic differentiation, including RUNX1, CEBPA, and GATA2 in MDS and AML, and PAX5 in acute lymphoblastic leukemia, indicate that disturbed hematopoietic stem cell dynamics may initiate leukemogenesis. On the other hand, for at least some leukemia-predisposing syndromes – including congenital neutropenia when caused by mutations in the gene, ELANE, encoding neutrophil elastase – terminal effectors of hematopoietic differentiation can lead to malignancy, implying that contributions to malignant transformation may go beyond the stem cell. The molecular genetic basis of hereditary leukemic disorders and how they mesh with current concepts of disease mechanism and other insights ensuing from cancer genome sequencing will be discussed.