Infection makes micro-CHIPs into macro-CHIPs

In this issue of Cell Stem Cell, Hormaechea-Agulla et al., 2021Hormaechea-Agulla D. Matatall K.A. Le D.T. Kain B. Long X. Kus P. Jaksik R. Challen G.A. Kimmel M. King K.Y. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFN? signaling.Cell Cell. 2021; (Published online March 19, 2021)https://doi.org/10.1016/j.stem.2021.03.002Abstract Full Text PDF Scopus (45) Google Scholar demonstrate that signaling following an in mice provides a selective pressure growth Dnmt3a?/? hematopoietic stem cells. This expansion is mediated by global methylation changes lead to increased self-renewing capacity. Hematopoietic cells (HSCs) accumulate somatic mutations over the course lifetime as result cell divisions and exogenous stressors. Although nearly all these have no fitness effect, certain confer advantages HSCs which they arise. These their progeny, referred “clone,” disproportionately expand time. With advent next-generation sequencing blood-derived DNA large cohort studies, prevalence mutational spectrum expansions humans has largely been determined. Unsurprisingly, increases with age: 10%–20% individuals 70 years or older harbor mutant clones. The genes most frequently mutated (DNMT3A, TET2, ASXL1) are also often found frank myeloid malignancies. presence blood associated risk developing hematological malignancies, vast majority people who them do not cancer. term indeterminate potential (CHIP) was coined distinguish pre-malignant state from seen setting malignancy (Jaiswal Ebert, 2019Jaiswal S. Ebert B.L. Clonal human aging disease.Science. 2019; 366: eaan4673Crossref PubMed (261) Scholar). Since discovery CHIP, major focus identifying modulators progression only minority elderly clones (defined arbitrarily greater than 4% cells) even smaller number develop cancer, intriguing research shown everyone middle-aged circulating (Young 2016Young A.L. Birmann B.M. Druley T.E. haematopoiesis harbouring AML-associated ubiquitous healthy adults.Nat. Commun. 2016; 7: 12484Crossref (346) begs question: what causes small into larger ones cause cancer some but others? To explore question, many groups employed phenotype-CHIP genotype studies cohorts identify any factors associate CHIP A recent theme emerging association chronic inflammation immune activation, such associations between various pro-inflammatory cytokines (Bick 2020Bick A.G. Weinstock J.S. Nandakumar S.K. Fulco C.P. Bao E.L. Zekavat S.M. Szeto M.D. Liao Leventhal M.J. Nasser J. al.NHLBI Trans-Omics for Precision Medicine ConsortiumInherited 97,691 whole genomes.Nature. 2020; 586: 763-768Crossref (144) Scholar; Cook 2019Cook E.K. Izukawa T. Young Rosen G. Jamali Zhang L. Johnson Bain E. Hilland Ferrone C.K. al.Comorbid inflammatory characteristics genetic subtypes hematopoiesis.Blood Adv. 3: 2482-2486Crossref (44) robust relationship systemic landscape, provide insight directionality association. Are producing cells, environment driving development CHIP? Initial lacking Tet2, second commonly gene had enhanced innate activation accelerated atherosclerosis 2017Jaiswal Natarajan Silver A.J. Gibson C.J. Bick Shvartz McConkey Gupta N. Gabriel Ardissino al.Clonal Hematopoiesis Risk Atherosclerotic Cardiovascular Disease.N. Engl. Med. 2017; 377: 111-121Crossref (957) However, more evaluated whether may play role Cai 2018Cai Z. Kotzin J.J. Ramdas Chen Nelanuthala Palam L.R. Pandey Mali R.S. Liu Y. Kelley M.R. al.Inhibition Inflammatory Signaling Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities Hematopoiesis.Cell 2018; 23: 833-849.e5Abstract (126) Meisel 2018Meisel Hinterleitner Pacis A. Earley Z.M. Mayassi Pierre J.F. Ernest J.D. Galipeau H.J. Thuille al.Microbial signals drive pre-leukaemic myeloproliferation Tet2-deficient host.Nature. 557: 580-584Crossref (172) demonstrated Tet2-KO survival advantage proliferative phenotype response challenges, resulting preferential IL-6 signaling. Furthermore, Heyde 2021Heyde Rohde McAlpine C.S. Hoyer F.F. Gerold J.M. Cheek Iwamoto Schloss Vandoorne K. al.Increased proliferation accelerates hematopoiesis.Cell. 184: 1348-1361.e22Abstract (51) illustrated elevated HSC challenge, atherosclerotic development, furthered thread elegantly demonstrating how promotes carrying loss-of-function DNMT3A Their previous experiments established Mycobacterium avium induced interferon gamma (IFN?)-mediated depleted normal (Matatall 2016Matatall Jeong Sun F. Mo Q. Infection Depletes through Terminal Differentiation.Cell Rep. 17: 2584-2595Abstract (122) Here, tested hypothesis would be resistant challenge. study used chimeric model where recipient were transplanted 10% 90% Dnmt3a+/+ then infected avium. experimental setup, noted significant phenotypically functionally defined multipotent progenitors (MPPs) treated Importantly, effect observed one functional copy Dnmt3a, similar situation mutations. Additionally, clonally expanding secondary stress-induced apoptosis retain self-renewal capacity longer compared wild-type HSCs. infection-induced did occur absence receptor, necessity process. exposure alone without sufficient induce Transcriptional epigenetic profiling revealed induces massive throughout genome Dnmt3a+/+, divergent transcriptional outcomes, repression differentiation-related Batf2, Jun, Fos. summary, Figure 1, leads Dnmt3a because terminal differentiation relatively (Hormaechea-Agulla impressive mechanistic suggests several testable predictions humans. First, history infections, tuberculosis, should higher hematopoiesis. Second, longitudinal analyses reveal strong markers clone growth. Finally, clinically important, treating underlying drugs lifestyle modifications slow prevent and, hence, decrease transformation If true, usher new era “preventative hematology” susceptible population. signalingHormaechea-Agulla al.Cell CellMarch 2021In BriefHormaechea-Agulla colleagues mycobacterial deficient Interferon promote expansion, broad regulation prodifferentiation program. Full-Text Open Archive