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Lanzavecchia A. Expression of two T cell receptor alpha chains: dual
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7. Wang C, Sanders CM, Yang Q, et al. High throughput sequencing
reveals a complex pattern of dynamic interrelationships among human T cell subsets. Proc Natl Acad Sci U S A. 2010;107(4):1518- 1523.
8. Ni PP, Solomon B, Hsieh CS, Allen PM, Morris GP. The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires. J Immunol. 2014;193(4):1778-1786.
9. Morris GP, Uy GL, Donermeyer D, Dipersio JF, Allen PM. Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease. Sci Transl Med. 2013;5(188): 188ra174.
10. Balakrishnan A, Gloude N, Sasik R, Ball ED, Morris GP. Proinflammatory Dual Receptor T Cells in Chronic Graft-versus- Host Disease. Biol Blood Marrow Transplant. 2017;23(11):1852- 1860.
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immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017;31 (5):1145-1153.
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Mosaicism by somatic non-functional mutations: one cell lineage at a time
Willy Albert Flegel1,2
1Department of Transfusion Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, MD and 2Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
E-mail: WILLY ALBERT FLEGEL - waf@nih.gov doi:10.3324/haematol.2018.208165
Somatic mutations are abundant in most cells of our tis- sues.1,2 The impact of any somatic mutation may be small and temporary if it occurs in differentiated cells without giving rise to malignant growth by unlocking their terminal differentiation. We expect a much wider and last- ing impact from the same somatic mutations if they occur during earlier steps of differentiation. If they arise in a stem or progenitor cell, a whole set of cells (the lineage down- stream of the progenitor) will be affected. Any such novel somatic mutation may stay with the individual for life, when different somatic mutations can accumulate in cell lineages over time.3 The combination of somatic mutations becomes not only part of our lives, but contributes to our phenotype.4 The variety of somatic mosaicism that will develop differs randomly among individuals and forms the basis of our healthy constitutions as well as of some med- ical conditions.
In this issue of the Journal, Dauber et al. present a techni- cally advanced study5 describing the molecular causes of mosaicism in 2 patients. The antigens of the Rhesus blood group system (ISBT 004) served as markers allowing the authors to take advantage of routine serology and detect affected individuals. The patients with red cell mosaicism were identified by the loss of the c antigen (RH4) in a subset of their red cells. The causes of this serological phenotype were traced to distinct precursor stages of myeloid and pluripotent stem cells, respectively.5 As the antigens were only the markers and not the focus, this study, at the inter-
section of ‘erythropoiesis gone wrong’ and red cell antigens, has relevance beyond blood groups and offers valuable information to the hematology community.
Red cell mosaicism was documented in leukemia for ABO antigens in 1957,6,7 and for Rh a few years later;8 it has been documented for various blood groups many times since then.5,9,10 During routine blood group typing world- wide, immunohematologists repeatedly encounter the inci- dental finding of a ‘mixed field’ agglutination or a discrep- ancy with previous results in the patient’s health record. In both patients of the current study,5 ‘mixed field’ agglutina- tion was observed and prompted further investigation. Barring technical issues with the serology, such findings are infrequent, although not rare, in the absence of transfu- sions. Many patients could be identified with mosaicism that cannot be explained simply by recent transfusion, and these patients could then be followed up in order to evalu- ate the clinical implications. Possible causes are loss of het- erozygosity (LOH) associated with loss of tumor suppres- sor gene functions,11 or copy-neutral LOH associated with the gain of oncogenic mutations.12,13
Despite the discrepancy in blood group, the immediate transfusion support given to these patients is usually straightforward. Hence, further analysis is not considered necessary within the practical approach to clinical care. The clinical prognosis of LOH in hematologically asymptomatic patients is currently unknown, although the authors point out that this may now be changing. The diagnosis of red
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