Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure

• Published in: JCI insight Vol. 5; no. 4
• Main Authors: Heidemann, Stephanie, Bursic, Brian, Zandi, Sasan, Li, Hongbing, Abelson, Sagi, Klaassen, Robert J., Abish, Sharon, Rayar, Meera, Breakey, Vicky R., Moshiri, Houtan, Dhanraj, Santhosh, de Borja, Richard, Shlien, Adam, Dick, John E., Dror, Yigal
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 27.02.2020
• Subjects: Bone marrow; Oncology; Hematology; Genetic diseases; Leukemias
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.131018

Inherited bone marrow failure syndromes, such as Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS), feature progressive cytopenia and a risk of acute myeloid leukemia (AML). Using deep phenotypic analysis of early progenitors in FA/SDS bone marrow samples, we revealed selective survival of progenitors that phenotypically resembled granulocyte-monocyte progenitors (GMP). Whole-exome and targeted sequencing of GMP-like cells in leukemia-free patients revealed a higher mutation load than in healthy controls and 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, and decreased mutation rates at Xp(C>T)pG sites compared with other Xp(C>T)pX sites and enrichment for Cancer Signature 1 (X indicates any nucleotide). Potential preleukemic targets in the GMP-like cells from patients with FA/SDS included SYNE1, DST, HUWE1, LRP2, NOTCH2, and TP53. Serial analysis of GMPs from an SDS patient who progressed to leukemia 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 2 FA/SDS patients with leukemia was similar to that of FA/SDS patients without transformation. The predicted founding clones in SDS-derived AML harbored mutations in several genes, including TP53, while in FA-derived AML the mutated genes included ARID1B and SFPQ. We describe 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.