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IMPLICATIONS OF REVERTANT SOMATIC MOSAICISM IN BONE MARROW FAILURE SYNDROMES

Authors :
Kerry Philips
Amee J George
Ben Saxon
Christopher P. Barnett
Ross D. Hannan
Andreas W. Schreiber
David Lawrence
Christopher N. Hahn
Jinghua Feng
Peter Wilson
Nicola Poplawski
Amanda Tirimacco
Richard J D'Andrea
Luen To
Anna L. Brown
Alexandra L. Yeoman
Parvathy Venugopal
Milena Babic
Chun Chun Young
Jesse Cheah
Sarah Moore
Michael Guandalini
Sarah C Bray
Hamish S. Scott
Miriam Fine
Source :
Experimental Hematology. 76:S90
Publication Year :
2019
Publisher :
Elsevier BV, 2019.

Abstract

Revertant somatic mosaicism (RM) has been reported in genetic diseases including skin disorders and bone marrow failure (BMF) syndromes. We present examples of RM of haematopoietic cells in the context of inherited BMF syndromes with dramatically different clinical outcomes. Diamond Blackfan Anaemia (DBA) is an inherited BMF disorder caused by mutations/deletions in ribosomal proteins. We have a 9 year old male who required regular transfusions until he became transfusion independent at age 4. We identified a 184kb deletion on chromosome 12 encompassing 11 genes including RPS26 (known DBA gene). Significantly, we observed multiple independent copy neutral loss of heterozygosity (CNLOH) events on chromosome 12, correcting the 184kb deletion in a subset of blood cells, but not in hair. We propose RM as a mechanism for correction of the germline deletion resulting in spontaneous remission in the patient. We also recently identified germline mutations in SAMD9L, in a family with thrombocytopaenia, macrocytosis and ALL. In this family, we see examples for somatic mosaicism leading to a severe blood phenotype as well as CNLOH RM causing milder phenotypes in different family members. RM needs to be considered when selecting tissue source for diagnosis in carriers with mild phenotype/remission, and use of patient-derived cell lines for drug screens with multiple rounds of cell replication. We are currently trying to understand and manipulate revertant clone selection and hope this will open windows for rational correction and selection protocols for effective therapeutic intervention. Experimental manipulations to select clones that improve clinical phenotype have substantive implications on efficiencies of gene manipulations, manufacture and quality control requirements of autologous cellular therapies.

Details

ISSN :
0301472X
Volume :
76
Database :
OpenAIRE
Journal :
Experimental Hematology
Accession number :
edsair.doi...........8745baeba7efd82ddbdf1546b512b6dc