Mutations that negatively impact mitochondrial function are highly prevalent in humans and lead to disorders with a wide spectrum of disease phenotypes, including deficiencies in immune cell development and/or function. Previous analyses of mice with a hepatocyte-specific cytochrome c oxidase (COX) deficiency revealed an unexpected peripheral blood leukopenia associated with splenic and thymic atrophy. Here, we use mice with a hepatocyte-specific deletion of the COX assembly factor Sco1 to show that metabolic defects extrinsic to the hematopoietic compartment lead to a pan-lymphopenia represented by severe losses in both B and T cells. We further demonstrate that immune defects in these mice are associated with the loss of bone marrow lymphoid progenitors common to both lineages and early signs of autoantibody-mediated autoimmunity. Our findings collectively identify hepatocyte dysfunction as a potential instigator of immunodeficiency in patients with congenital mitochondrial defects who suffer from chronic or recurrent infections.
© 2025 The Author(s).

Abstract RNA binding proteins (RBPs) have been reported to own genome-wide chromatin binding sites, and are supposed to regulate transcription directly. However, the molecular detail about RBPs regulating transcription is still unclear. Here, we showed the RBP AKAP95 engaged in transcription regulation through tethering itself to nascent RNA on chromatin. Further, phase separation enabled AKAP95 having large spectrum coverage on transcription start sites and meanwhile recruiting RNA polymerase II CTD to activate transcription. This transcription co-activation mechanism was hijacked in MLL rearranged (MLLr) leukemia. AKAP95 was enclosed in the same condensates with MLL1 translocated fragment. It was required for MLLr leukemogenesis, but not for normal and regenerative hematopoiesis, rendering AKAP95 an ideal target for leukemia therapeutics. As an endeavor for modifying condensates, we designed a peptide bridging AKAP95 with protein quality surveillance component HSP70. This peptide successfully impaired AKAP95 phase separation, transcription activation and cancer cell growth, attesting the concept that oncogenic condensates is druggable.

Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
© 2024 The Authors.

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.
© 2024. The Author(s).

Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.