Inherited bone marrow failure syndromes (IBMFSs) 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 to other Xp(C>T)pX sites and enrichment for Cancer signature 1 (X indicates any nucleotide). 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 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 two FA/SDS patients with leukemia was similar to that of FA/SDS patients 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. 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.
Related Posts
Advertisement
Meeting Coverage
- ASCO – Lung CancerASCO.20 Virtual Scientific Program, held May 29 - 31, brought professionals from all over the world together to hear the brightest minds in oncology present state-of-the-art treatment modalities and new therapies.
- AACR-2020The American Association for Cancer Research is the world's oldest and largest professional association related to cancer research.
- ACC 2020The American College of Cardiology decided to cancel ACC.20/WCC due to COVID-19, which was scheduled to take place March 28-30 in Chicago. However, ACC.20/WCC Virtual Meeting continues to release cutting edge science and practice changing updates for cardiovascular professionals on demand and free through June 2020.
- ASCO 2019The 2019 ASCO Annual Meeting, taking place May 31-June 4 in Chicago, will bring together more than 32,000 oncology professionals from across the globe. The theme of this year’s conference is Caring for Every Patient, Learning From Every Patient.