Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.

Acute lymphoblastic leukemia (ALL) diagnosed within the first month of life is classified as congenital ALL and has a significantly worse outcome than ALL diagnosed in older children. This suggests that congenital ALL is a biologically different disease, and thus may be caused by a distinct set of mutations. To understand the somatic and germline mutations contributing to congenital ALL, the protein-coding regions in the genome were captured and whole-exome sequencing was employed for the identification of single-nucleotide variants and small insertion and deletions in the germlines as well as the primary tumors of four patients with congenital ALL.

Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).

Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating posttransplant immune suppression. Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase and telomere lengths (TLs) shorten with natural aging and DNA damaging processes. It is possible that, if CHIP is present before ASCT-GT or mutagenesis occurs after busulfan exposure, the hematopoietic stem cells carrying these somatic variants may survive the conditioning chemotherapy and have a selective reconstitution advantage, increasing the risk of hematologic malignancy and overall mortality. Seventy-four peripheral blood samples (ranging from baseline to 120 months after ASCT-GT) from 10 pediatric participants who underwent ASCT-GT for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) after reduced-intensity conditioning with busulfan and 16 healthy controls were analyzed for TL and CHIP. One participant had a significant decrease in TL. There were no CHIP-associated mutations identified by the next-generation sequencing in any of the ADA-SCID participants. This suggests that further studies are needed to determine the utility of germline analyses in revealing the underlying genetic risk of malignancy in participants who undergo gene therapy. Although these results are promising, larger scale studies are needed to corroborate the effect of ASCT-GT on TL and CHIP. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool. Following myelosuppressive irradiation, PTN expression is increased in bone marrow endothelial cells (BMECs), and PTN+ ECs are more frequent in the niche. Moreover, deleting Ptn from ECs impairs HSC regeneration whereas Ptn deletion from BM stromal cells does not. These findings reveal dichotomous and complementary regulation of HSC maintenance and regeneration by BM stromal cells and ECs.