With the interplay of germline and somatic genetics being increasingly recognized as a critical factor for the biology of various hematopoietic malignancies, adequate detection of both is critical. Towards that, in a review, Godley described the combination of germline genetic testing with tumor-based profiling in blood cancers for accurate risk assessment and treatment planning. The original research article by Perani et al. complimentarily highlights the importance of using appropriate biological samples to confirm germline variants, to enable adequate treatment planning early on. They compared sequencing data from bone marrow, blood, saliva, skin fibroblasts and hair follicles in a group of 29 patients and 44 relatives. The study revealed limitations in saliva testing due to tumor cell infiltration, while hair follicle DNA extraction showed potential as an alternative to skin biopsy.

Over 100 genes have been associated with inherited BMF, and continued research is needed to fully understand their role in disease development and progression. Feurstein conducted a comprehensive review on four recently identified BMF syndromes involving genes ERCC6L2, MECOM, DNAJC21, and ADH5/ALDH2. Additionally, a new gene, called Replication protein A1 (RPA1) has recently been identified to cause TBD. In a brief research report, Sharma et al. found significant enrichment of novel and ultra-rare germline RPA1 variants in solid tumors, brain cancer, and hematological malignancies, suggesting a potential link between RPA1 variants and predisposition to pediatric cancer.

Treating BMF and hematopoietic malignancies that arise in the background of an underlying germline predisposition syndrome remains a complex and evolving topic. The mini-review by Bhoopalan et al. discusses important considerations for DBA patients and caregivers when deciding on HSCT. Factors like age, transfusion dependence, steroid response, and iron overload should be considered for eligibility. Gene correction by lentiviral vectors with GATA1 gene overexpression or CRISPR/Cas9are promising alternative strategies. However, practical obstacles like limited access to stem cells, long-term efficacy and safety need to be addressed through further research and clinical trials. The second mini-review by Toya et al. specifically delves into adult-onset hereditary myeloid malignancies (HMM). The review highlights the challenges related to diagnosis, optimal treatment strategies, uncertainties regarding the timing and indication for HSCT, the risk of donor cell leukemia, and the absence of a recommended conditioning regimen for HMMs, emphasizing the need for further research to improve patient management in this area.

An important aspect of this Research Topic is exploring dysregulated molecular pathways in BMF and blood cancers for potential targeted therapy. This topic is covered by three systematic reviews and one original research article. The first review by Shinriki and Matsui provides an overview of DDX41 mutations, which are found in approximately 2-5% of acute myeloid leukemia and myelodysplastic syndrome (MDS) patients. The review explores the role of DDX41 in various processes such as RNA splicing, DNA sensing in innate immunity, R-loop regulation, ribosome biogenesis, and translation. It also highlights the need for alternative treatments utilizing synthetic lethality, particularly for elderly patients who have difficulty with traditional cytotoxic chemotherapy. The second review by Jia and Gu discusses PAX5 gene alterations and their impact on B-cell acute lymphoblastic leukemia. The third review by Nasr and Filippi highlights the emerging role of mitochondria in the development of BMF and MDS, emphasizing the impact of abnormal mitochondrial metabolism, dynamics and reactive oxygen species on ineffective hematopoiesis. In the final article of this Research Topic, Mochizuki-Kashio et al. conducted an original research exploring the effects of replication stress (RS) on mitochondrial function in a Fancd2-deficient FA mice model. The study revealed RS to affect mitochondrial activity and mitophagy in Fancd2-deficient fetal hematopoietic stem cells (HSCs) and adult bone marrow HSCs, pointing to mitochondrial metabolism defect in FA pathophysiology.