Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome

Abstract

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Keywords: AML; DDX41; HHMS; MDS; SAMD9; SAMD9L; TP53; germline; variant.

Figure 1

Involvement of DDX41 variants in myeloid leukemogenesis. (A) Myeloid neoplasms arising from DDX41 variants: Hematopoietic cells carrying a heterozygous germline DDX41 variant (depicted as cells with blue nuclei) undergo the development of myeloid neoplasms following the acquisition of a somatic variant in the initially wild-type DDX41 after a prolonged latent period (illustrated as cells with light purple nuclei). The proportion of tumor cells tends to be low, and these cells may disrupt normal hematopoiesis, which is sustained by cells with only a germline variant. (B) Effects of R-loop accumulation on cellular function: R-loops form when transcribed RNA hybridizes with template DNA. The inappropriate accumulation of R-loops leads to DNA replication stress, impacting cellular function.

Figure 2

Role of p53 variants in cancer. p53 variants produce drug resistance, dominant negative effects on wild-type p53, proteasome repression, and LOF of wild-type p53. In cases of GOF, it promotes various cellular responses such as carcinogenesis, cancer cell proliferation, invasion, metastasis, tumor microenvironment establishment, genomic instability, and metabolic reprogramming.

Figure 3

Role of SAMD9 and SAMD9L in HSPC function. The SAMD9 and SAMD9L genes regulate proteins involved in the cell cycle, DNA damage repair, and ribosome regulation. Mutant SAMD9 and SAMD9L proteins significantly enhance these functions, which cause decreased hematopoietic potential and apoptosis in the bone marrow, promoting monosomy 7/del 7 HSPC production. Hematopoietic stem and progenitor cell (HSPC), myelodysplastic syndrome (MDS), and mutant type (MT).