Abstract
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.
Highlights
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a spectrum of hematopoietic disorders
We found that the granulocyte-monocyte progenitor–like (GMP-like) population is relatively preserved compared with marked exhaustion of other cell populations and carries a high mutation load and a unique trinucleotide mutation signature, suggesting that granulocyte-monocyte progenitors (GMP)-like cells are a reservoir for clonal evolution
hematopoietic stem cell (HSC) and multipotent progenitors are markedly reduced in Fanconi anemia (FA)/ShwachmanDiamond syndrome (SDS)
Summary
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a spectrum of hematopoietic disorders. Despite intensive chemotherapy and hematopoietic stem cell (HSC) transplantation, the overall survival of advanced MDS/AML remains low, approximately 60% in children and approximately 30% in adults [1]. Hematopoiesis is a complex developmental system that is organized as a hierarchy sustained by multipotent HSCs. typically depicted with increasingly restricted oligopotent and unipotent progenitors downstream of HSCs, recent studies demonstrate a reshaping of the architecture of human hematopoietic hierarchy between in utero fetal liver and adulthood time points [3,4,5]. Transcriptional and functional analysis suggests that by adulthood, there is predominantly a 2-tier hierarchy of multipotent and unipotent human stem progenitor stem cells (HSPCs) [5]
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