Advances in germline predisposition to acute leukaemias and myeloid neoplasms

Abstract

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.

Figure 1.. Association of germline mutations in genes encoding transcription factors with lineage development.

The representative schematic of the hierarchy of hematopoietic development demonstrates the main hematopoietic lineages that are dysregulated in patients with germline mutations in different transcription factors important in hematopoietic growth and differentiation. Germline alterations in ETV6 and TP53 can lead to hematopoietic neoplasms in both myeloid and lymphoid lineages, while disruptions in the genes encoding other hematopoietic transcription factors result in more lineage-restricted malignancies (e.g. B-ALL with PAX5 or AML with CEBPA). tMN: Therapy-related myeloid neoplasm; LH: Low hypodiploid.

Figure 2.. Genetics of cancer predisposition genes in pediatric myeloid disorders malignancies

Schematics and domain architectures of proteins encoded by genes that have germline and somatic mutations in pediatric myeloid disorders, including GATA2 (a), SAMD9 (b), and SAMD9L (c) are shown. Refseq identifiers for transcripts used to generate the protein schematics are shown under the gene symbols. Listed germline mutations in GATA2 were collected from ref and from available Pathogenic and Likely Pathogenic variants from ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). SAMD9 and SAMD9L variants were taken from refs. ^,–,,–. ZnF, zinc finger; NTPase, nucleoside triphosphatase; SAM, sterile alpha motif; AlbA, acetylation lowers binding affinity; SIR-2, silent information regulator 2; APAF-1, apoptotic protease-activating factor, TPR tetratricopeptide repeat; OB Fold, oligonucleotide/oligosaccharide-binding fold. SAMD9 and SAMD9L domain structure obtained from ref. .

Figure 3.. Genetics of cancer predisposition genes in pediatric acute lymphoblastic leukemia

Schematics and domain architectures of proteins encoded by genes harboring germline and somatic mutations in pediatric acute lymphoblastic leukemia (ALL), including PAX5 (a), TP53 (b) and IKZF1 (c). The germline mutations are shown below the protein schematic and the somatic mutations on top. (a) PAX5 somatic variants are predominantly missense variants in the DNA binding domain and truncations that remove the transactivation domain. By contrast, a single residue has been observed mutated in familial ALL, G183S in the octapeptide domain. (b) Germline TP53 variants are shown for hypodiploid ALL, which involve the DNA binding domain and nuclear localization sequences. (c) Differences in distribution in IKZF1 variants are observed between germline and somatic variants. Somatic variants are most commonly N terminal truncating mutations, DNA binding domain missense mutations (most commonly in the second and third DNA-binding zinc fingers (ZnFs), which are required for DNA binding), and distal truncating and C-terminal ZnF missense mutation. In contrast, germline variants are predominantly located outside of ZnFs (possibly as these would not be tolerated as germline events) but in functional assays such as protein localization, adhesion and drug resistance, are commonly as deleterious or more deleterious than somatic variants. Germline data taken from refs ^,,; somatic mutation data updated from ref. .

Figure 4.. Model of disease progression.

Progression to advanced disease occurs through multiple different and potentially overlapping mechanisms in patients with MDS or acute leukemia predisposition syndromes. The pathways commonly observed for the different germline predispositions (genes highlighted on the right) are shown. Progression to advanced disease in many predisposition syndromes occurs through a step wise process involving loss of the remaining wild-type allele and acquisition of additional cooperating mutations (top), while others appear to maintain the wild-type allele (middle). SAMD9 and SAMD9L are unique in that disease progression is observed when there is outgrowth of monosomy 7 cells that lack the deleterious germline mutation and then cells can acquire additional somatic mutations for the full disease phenotype.