title: BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans.
abstract: Human blood cell counts are tightly maintained within narrow physiologic ranges, largely controlled by cytokine-integrated signaling and transcriptional circuits that regulate multilineage hematopoietic specification. Known genetic loci influencing blood cell production account for <10% of platelet and red blood cell variability, and thrombopoietin/cellular myeloproliferative leukemia virus liganding is dispensable for definitive thrombopoiesis, establishing that fundamentally important modifier loci remain unelucidated. In this study, platelet transcriptome sequencing and extended thrombocytosis cohort analyses identified a single loss-of-function mutation (BLVRB(S111L)) causally associated with clonal and nonclonal disorders of enhanced platelet production. BLVRB(S111L) encompassed within the substrate/cofactor [α/β dinucleotide NAD(P)H] binding fold is a functionally defective redox coupler using flavin and biliverdin (BV) IXβ tetrapyrrole(s) and results in exaggerated reactive oxygen species accumulation as a putative metabolic signal leading to differential hematopoietic lineage commitment and enhanced thrombopoiesis. These data define the first physiologically relevant function of BLVRB and implicate its activity and/or heme-regulated BV tetrapyrrole(s) in a unique redox-regulated bioenergetic pathway governing terminal megakaryocytopoiesis; these observations also define a mechanistically restricted drug target retaining potential for enhancing human platelet counts.
authors.affiliation: Department of Applied Mathematics and Statistics.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Medicine, and.
authors.forename: Zongdong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, and.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Gnatenko
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY; and.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Applied Mathematics and Statistics.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, and.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Malone
authors.affiliation: Department of Medicine, and.
authors.forename: Nedialka
authors.initials: N
authors.lastname: Markova
authors.affiliation: Department of Biochemistry, Trinity College, Dublin, Ireland.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mantle
authors.affiliation: Department of Medicine, and.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Nesbitt
authors.affiliation: Department of Medicine, and.
authors.forename: Wadie F
authors.initials: WF
authors.lastname: Bahou
mesh_terms: D000483:Alleles; D018952:Antigens, CD34 / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D019070:Cell Lineage; D015331:Cohort Studies; D041905:Erythroid Cells / Q000166:cytology / Q000201:enzymology; D056726:Genetic Association Studies; D006410:Hematopoiesis; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000201:enzymology; D053858:Metabolic Networks and Pathways; D009154:Mutation / Q000235:genetics*; D010084:Oxidation-Reduction; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D017423:Sequence Analysis, RNA; D013922:Thrombocytosis / Q000235:genetics; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D017382:Reactive Oxygen Species; D006418:Heme; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase