Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.
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The authors thank I. Iacobucci for assistance with figure preparation. The authors are supported by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, the St. Jude Comprehensive Cancer Center (Core Grant CA021765), the National Heart, Lung, and Blood Institute (NHLBI) (R01 HL144653 to J.M.K.), the Edward P. Evans Foundation (to J.M.K.), the National Cancer Institute (NCI) (R35 CA197695 to C.G.M.), the Henry Schueler 19 Foundation (to C.G.M.) and a St. Baldrick’s Foundation Robert J. Arceci Innovation Award (to C.G.M.).
C.G.M. has received research funding from Loxo Oncology, Pfizer and AbbVie; has received speaking and travel fees from Amgen; holds stock in Amgen; and has been compensated for advisory board participation for Illumina. J.M.K. declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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- Clonal haematopoiesis
The expansion of a clonal population of haematopoietic cells marked by somatic mutations.
- Cytopenic phase
A period marked by a decrease in peripheral blood cell counts (anaemia, red blood cells; thrombocytopenia, platelets; leukopenia, white blood cells).
A decrease in monocytes.
- Pulmonary alveolar proteinosis
A lung disease characterized by a build-up of proteins and lipids in the functional units of the lung (alveoli) that is part of MonoMac syndrome, which results from GATA2 germline mutations.
- Sensorineural deafness
A form of hearing loss that results from damage to the inner ear or auditory nerve that is part of Emberger syndrome, which results from GATA2 germline mutations.
- Thrombocytopenia 2
An autosomal dominant syndrome resulting from germline mutations in ANKRD26 that is characterized by lifelong mild-to-moderate thrombocytopenia and an increase in the risk for myeloid malignancies.
- Philadelphia chromosome-like ALL
A group of B lymphoblastic leukaemias that have a global expression profile similar to BCR–ABL1-positive (Ph+) acute lymphoblastic leukaemia (ALL) but have alterations in other kinase signalling and cytokine receptor pathways.
- Ataxia telangiectasia
An autosomal recessive condition caused by mutations in the ATM gene. This syndrome is characterized by immunodeficiency, decreased DNA damage repair and neurological abnormalities.
- Nijmegen breakage syndrome
An autosomal recessive disorder that leads to chromosomal instability and is clinically characterized by microcephaly, growth retardation, immunodeficiency and predisposition to cancer.
- Robertsonian translocation
A non-reciprocal chromosomal translocation in which the long arms of two distinct acrocentric chromosomes become fused and share a single centromere.
- Ring chromosome
An abnormal chromosome in which the ends of a single chromosome fuse to form a ring.
- Li–Fraumeni syndrome
An autosomal dominant condition caused by an inherited mutation in TP53 that renders humans highly susceptible to numerous cancers, including breast cancer, leukaemia and sarcoma.
- BCR–ABL1-positive (Ph+) B-ALL
A class of B cell acute lymphoblastic leukaemia (B-ALL) haematopoietic disorders driven by the BCR–ABL1 fusion oncoprotein.
- Optical mapping
An approach to genome assembly in which DNA molecules are fluorescently labelled and imaged to construct maps.
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Klco, J.M., Mullighan, C.G. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer 21, 122–137 (2021). https://doi.org/10.1038/s41568-020-00315-z