Highlights d L-lactate triggers ER Mg 2+ release that promotes mitochondrial Mg 2+ uptake d Mg 2+ is a second messenger for metabolic circuits d Limiting Mrs2-mediated Mg 2+ uptake enhances mitochondrial bioenergetics d Inflammation-induced lactate contributes to organ failure via m Mg 2+ surge
Inherited bone marrow failure syndromes (IBMFSs) such as Fanconi Anemia (FA) and Shwachman-Diamond syndrome (SDS) feature progressive cytopenia and a risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Using deep immunophenotypic analysis of hematopoietic stem cells (HSCs) and early progenitors in bone marrow samples from 13 FA/SDS patients without MDS/AML and 6 healthy controls, we revealed relative survival of progenitors that phenotypically resembled granulocyte-monocyte progenitors (GMP) in the patients. In contrast, HSCs, multipotent progenitors, common myeloid progenitors and megakaryocyte-erythroid progenitors were remarkably reduced in FA/SDS patients compared to controls. Whole exome and targeted sequencing of GMP-like cells in leukemia-free patients revealed a prominently higher mutation load in FA/SDS patient samples than in healthy controls. Patient samples also manifested molecular changes that are characteristic of AML: increased G>A/C>T variants, decreased A>G/T>C variants, increased trinucleotide mutations at Xp(C>T)pT, decreased lower mutation rates at Xp(C>T)pG sites compared to other Xp(C>T)pX sites and enrichment for cancer signature 1. AML cells have previously been reported as commonly harboring this cancer signature. Potential pre-leukemic targets in the GMP-like cells from FA/SDS patients included SYNE1, DST, HUWE1, LRP2, NOTCH2 and TP53. Serial analysis of GMPs from a SDS patient, who progressed to AML revealed a gradual increase in mutational burden, enrichment of G>A/C>T signature and emergence of new clones. Interestingly, the molecular signature of marrow cells from two FA/SDS patients with AML was similar to that of FA/SDS without transformation. The predicted founding clones in SDS-AML harbored mutations in several genes including TP53, while in FA-AML the mutated genes included ARID1B and SFPQ. In conclusion, we described an architectural change in the hematopoietic hierarchy of FA/SDS with remarkable preservation of GMP-like populations harboring unique mutation signatures. GMP-like cells might represent a cellular reservoir for clonal evolution.
Disclosures
No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.