Rare patient populations in France and Finland reveal that gene mutations resulting in defective NER predispose to hematopoietic malignancies. Patients with XP are extremely sensitive to UV radiation from the sun and develop skin cancers and other problems as outlined. Homozygous founder mutations in genes encoding NER components lead to genetic susceptibility to hematopoietic malignancies: XP-C^delTG in descendants of North African immigrants to France and ERCC6L2^1457delT within the Finnish population. XP-C is the first NER protein to bind the damaged DNA, beginning a cascade of reactions resulting in an excised DNA fragment, repair of the gap, and resolution of the initial lesion, as shown in the inset. ERCC6L2 is part of transcription-coupled repair. When these critical NER components are absent (as is the case for homozygous XP-C^delTG mutations) or truncated prematurely (as is the case for homozygous ERCC6L2^1457delT mutations), TP53 mutations occur and drive leukemia development. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; T-cell ALL, T-cell acute lymphoblastic leukemia. Professional illustration by Luk Cox, Somersault18:24.