Abstract
Spontaneous Rh blood group changes are a striking sign, reported to occur mainly in patients with hematologic disorders. Upon routine blood grouping, 2 unrelated individuals showed unexplained mixed red cell phenotype regarding the highly immunogenic c antigen (RH4), clinically relevant for blood transfusion and fetomaternal incompatibility. About half of their red cells were c-positive, whereas the other half were c-negative. These apparently hematologically healthy females had no history of transfusion or transplantation, and they tested negative for chimerism. Genotyping of flanking chromosome 1 microsatellites in blood, finger nails, hair, leukocyte subpopulations, and erythroid progenitor cells showed partial loss of heterozygosity encompassing the RHD/RHCE loci, spanning a 1p region of 26.7 or 42.4 Mb, respectively. Remarkably, in one case this was detected in all investigated tissues, whereas in the other, exclusively myeloid cells showed loss of heterozygosity. Both carried the RhD-positive haplotypes CDe and the RhD-negative haplotype cde. RHD/RHCE genotypes of single erythroid colonies and dual-color fluorescent in situ hybridization analyses indicated loss of the cde haplotype and duplication of the CDe haplotype in the altered cell line. Accordingly, red cell C antigen (RH2) levels of both propositae were higher than those of heterozygous controls. Taken together, the Rhc phenotype splitting appeared to be caused by deletion of a part of 1p followed by duplication of homologous stretches of the sister chromosome. In one case, this phenomenon was confined to myeloid stem cells, while in the other, a pluripotent stem cell line was affected, demonstrating somatic mosaicism at different stages of ontogenesis.Introduction
Antigens of the Rh blood group system are very immunogenic and routinely typed in pretransfusion testing and prenatal investigations, as antibodies against these structures may elicit hemolytic transfusion reactions or hemolytic disease of the fetus and newborn. D (RH1) and c (RH4) are clinically the most important Rh antigens, as the frequently encountered anti-D and anti-c alloantibodies have pronounced hemolytic potential. All Rh antigens reside on RhD and RhCcEe polypeptides encoded by the RHD and RHCE genes, respectively, mapped to the short arm of chromosome 1 (p34-36).21
Unambiguous Rh typing is mandatory to account for the clinical relevance of these antigens. However, Rh-mismatched transfusion or hematopoietic stem cell transplantation (iatrogenic chimerism) may lead to concurrent presence of Rh antigen-positive and -negative red blood cells (RBCs) in the circulation. Importantly, mixed-field agglutination in serological Rh typing was noted also in non-iatrogenic settings, usually regarding the D antigen (and often haplo-typically linked C or E antigens). Apart from inborn forms of chimerism,3 acquired Rh antigen loss was preferentially observed in patients with clonal myeloid diseases,114 in some cases with cytogenetic chromosome 1 alterations.1412 Also hematologically healthy subjects were observed to have this phenomenon.18144 As the dominant mechanism of acquired Rh phenotype splitting, mosaicism based on myeloid lineage-restricted loss of heterozygosity (LOH) of variable stretches of chromosome 1 was identified with loss of one RH haplotype.4 In one case, somatic RHD mutation was described,19 whereas in other cases, RHD and RHCE gene deletion was reported.21204
In this study, the phenotypic and molecular characteristics of spontaneous c antigen anomaly in 2 unrelated individuals were investigated. For the first time, data are provided that demonstrate two different forms of somatic chromosome 1 mosaicism at different stages of ontogenetic development, as evidenced by involvement of different cells and tissues. The clinical significance of this phenomenon with regard to transfusion medicine and as a potential marker for hemato-oncologic disease is discussed.
Methods
Patients
Two female Caucasoid individuals (proposita A and proposita B, aged 69 and 35 years, respectively) from Switzerland without any history of transfusion or hematopoietic stem cell transplantation, came to attention with unexplained mixed-field agglutination in routine serological blood group typing. The latter was performed in the course of pretransfusion testing for knee surgery (proposita A) and as part of routine pregnancy monitoring (proposita B). This study was approved by the Swiss Red Cross Institutional Review Board. Written informed consent was obtained for extended testing and inclusion in this investigation.
Serological blood group typing and red cell flow cytometry
Serological blood group typing, anti-erythrocyte antibody screening and direct antiglobulin testing was carried out using gel centrifugation technique (Bio-Rad, Cressier, Switzerland), as described.22 In addition, monoclonal anti-c reagents from Diagast (Loos, France), BAG (Lich, Germany), Immucor (Rödermark) and Ortho Clinical Diagnostics (Neckargemünd, Germany) were used.
Expression of c and C antigens of RBCs from both propositae and of control red blood cell (RBC) samples was determined by flow cytometry (FACSCalibur with CellQuest software, BD Biosciences, San Jose, CA, USA) after indirect immunofluorescence staining with polyclonal anti-c and anti-C reagents (Molter, Neckargemünd, Germany).
Sorting of nucleated cell subsets from peripheral blood
Cell subsets of ethylenediamine tetraacetic acid (EDTA)-anticoagulated blood samples were quantified and sorted as previously described.234
Erythropoietic burst forming unit cultures
Cultures for erythropoietic burst-forming units (BFU-E), scoring and individual clonal picking for subsequent DNA isolation was performed as previously described.4
DNA isolation
Genomic DNA from EDTA-anticoagulated blood was extracted with the GenoPrep Cartridge B 350 on a GenoM-6 instrument (GenoVision, Vienna, Austria). DNA from buccal swabs, hair samples, finger nails, and single BFU-E colonies with the Qiamp DNA Investigator or Mini Kit (Qiagen, Valencia, CA, USA). DNA from sorted peripheral blood cells was extracted with Chelex.24
Molecular blood group RH genotyping
For RHD and RHCE genotyping, testing for variant RHD alleles and RHD zygosity of blood samples, polymerase chain reaction (PCR) kits (RBC Ready Gene CDE, Zygofast or RHd, Innotrain, Kronberg, Germany) were used.25 The RHCE*c allele was detected from DNA isolated from single BFU-E colonies with sequence specific monoplex real-time PCR using primers, probes and real-time PCR reagents as previously described,26 with a modified cycle protocol for increased sensitivity.
Microsatellite analysis
DNA prepared from whole blood and hair roots was tested in a multiplex-PCR of 15 highly polymorphic autosomal microsatellite loci to check for the existence of a possible chimerism (AmpFlSTR IDentifiler PCR Amplification Kit, Applied Biosystems, Foster City, CA, USA).
DNA samples from whole blood, buccal swabs (only proposita B), single hairs roots, nucleated blood cell subsets, or BFU-E colonies were analyzed with up to 16 different primer pairs targeting polymorphic dinucleotide microsatellite markers located on chromosome 1.
Fluorescence in situ hybridization analyses
Dual-color fluorescence in situ hybridization (FISH) analyses on fixed peripheral blood cells of both propositae were performed as previously described.4 P1-based artificial chromosome clones that encompass the RHD/RHCE and AF1q gene loci, respectively, were used. At least 200 cells per proband were scored and the signal patterns recorded separately for segmented and round nuclei.
Results
Spontaneous Rh blood group anomaly in 2 unrelated individuals
Routine serological blood group determination revealed unexpected mixed-field agglutination with respect to c antigen typing in 2 unrelated females without known hematologic disorder (proposita A and B). This was evident with all employed anti-c typing reagents (six monoclonal and one polyclonal). The proportion of c-positive red cells by flow cytometry was 53% and 50% in proposita A and B, respectively (Table 1). Apart from this, both individuals showed a normal C+D+E-e+ Rh phenotype. All other tested blood groups (ABO, MNS, P1Pk, Lutheran, Kell, Duffy, Kidd) were of normal phenotype (Table 1). No unexpected red cell antibodies were found in the plasma of these individuals, and the direct antiglobulin test with their erythrocytes was negative.
Routine RHD/RHCE genotyping combined with RHD zygosity determination of blood-derived DNA from both propositae yielded RHD heterozygosity (Dd) and predicted common Ccee phenotypes.
The c antigen quantities of their c-positive RBC subsets were similar to CcDdee phenotype control RBCs (Figure 1). Antithetical C antigen expression of both propositae was higher than in CcDdee controls, approaching the higher quantities seen in CCDDee controls (Figure 2).
Exclusion of congenital or acquired chimerism as cause of Rh phenotype anomaly
Twin chimerism or dispermy, as well as artificial chimerism (due to blood transfusion or organ transplantation) could be the reason for mixed blood group phenotypes. However, both propositae denied having a twin or a history of blood transfusions or organ grafts. Moreover, the analysis of 15 microsatellite loci with DNA of whole blood (loci located on chromosomes 2-5, 7, 8, 11-13, 16, 18, 19, and 21) ruled out chimerism: exclusively homozygous or well-balanced heterozygous allelic peaks were found, with a maximum of two alleles present at each locus (data not shown).
Loss of heterozygosity on chromosome 1 at an early stage of ontogenetic development in proposita A
As the RHD/RHCE loci are located on the short arm of chromosome 1, the possibility of mosaicism was tested by use of heterozygous chromosome 1 microsatellite markers (for full details, see the Online Supplementary Appendix). In proposita A, the analysis of D1S468 (21 Mb telomeric of RH*D), D1S234 (0.5 Mb telomeric of RH*D), and D1S233 (5.7 Mb centromeric of RH*D) using DNA from whole blood, and sorted leukocyte subpopulations (CD4 T cells, CD8 T cells and granulocytes) showed in all samples a clear-cut imbalance of the peak heights. This indicated the presence of 2 cell populations in which 1 lost one 1p segment. Such an LOH was also seen in 2 of 6 single hair roots. The analysis of DNA from 19 BFU-E colonies showed that 9 had complete LOH.
Other microsatellite loci more centromeric than D1S233 were also tested, without evidence for LOH. The minimal expansion of LOH on 1p of the affected cell lines amounted to at least 26.7 Mb (Figure 3).
Loss of heterozygosity on chromosome 1 confined to myeloid cells in proposita B
In proposita B, the analysis of microsatellites in the region between D1S507 (10.3 Mb telomeric of RH*D) and D1S2890 (32.1 Mb centromeric of RH*D) using DNA from whole blood showed in all samples a peak height imbalance diagnostic of LOH, thus demonstrating the existence of 2 cell populations in which 1 lost 1 allele. D1S252 located centromeric of D1S2890 exhibited no LOH. Hairs showed no LOH in all loci tested.
The alleles of D1S2890 were further investigated using DNA from buccal swab, single hair roots, sorted leukocyte subpopulations (CD4 T cells, CD8 T cells, and granulocytes), and BFU-E colonies. A myeloid lineage-restricted pattern of LOH was found, with LOH detected in sorted granulocytes and in 4 out of 22 BFU-E colonies. In contrast, hairs (n=3), buccal cells, and lymphocyte subsets showed no LOH (Figure 3). Further details of these analyses are provided in the Online Supplementary Appendix.
RH genotype splitting confirmed by molecular analysis of single erythroid progenitor cells
DNA samples from separate BFU-E colonies were subjected to real-time PCR genotyping for RHCE*c. Six BFU-E samples each of both individuals with mixed Rhc phenotype were analyzed and displayed a similar pattern: 3 out of 6 tested BFU-E DNA samples showed heterozygous results for the RHCE*c allele; in contrast, the other half indicated LOH at this locus (Table 2). Importantly, only BFU-E colonies with RHCE*c heterozygosity were found to be also heterozygous for RHD (Dd), whereas LOH was uniformly associated with homozygous or potentially hemizygous RHD-positive typing (DD or D-) (Table 2). These results underlined the haplotypic nature of the observed blood group anomaly and indicated the co-existence of 2 RBC lines: 1 of normal c-positive phenotype encoded by 2 parental RH haplotypes (CDe/cde) and a second with c-negative phenotype encoded by the LOH-modified RHCE*c-negative parental haplotype only (homozygous CDe/CDe or hemizygous CDe/---).
Rh blood group anomaly caused by somatic recombination-associated duplication
To determine whether the Rhc-negative cell clone resulted from a hemizygous deletion (CDe/---) or a more complex somatic recombination-associated duplication of the CDe haplotype, dual-color FISH analyses on fixed peripheral blood cells obtained from both studied individuals were performed. In both proposita A and B, FISH analysis showed the diploid presence of the RH loci in all segmented and round nuclei (Figure 4). Despite there being no proof by chromosomal sequencing, these results indicated somatic recombination-associated loss of the RHCE*c-positive/RHD-negative and duplication of the RHCE*c-negative/RHD-positive haplotype as cause for the observed RBC phenotype splitting. Hence, the LOH-affected RHCE*c-negative cell lines of both propositae most probably harbored homozygous CDe/CDe haplotypes.
Discussion
Two individuals with an unexplained mixed-field agglutination in routine serological Rhc typing have been observed. Common causes of mixed Rhc phenotype, such as RBC transfusion or hematopoietic stem cell transplantation, were ruled out in the 2 propositae. Extended molecular testing was performed to define the underlying mechanism of this condition. Microsatellite analysis across different chromosomes excluded spontaneous chimerism known to bring about mixed blood group phenotypes.27
Using chromosome 1 microsatellite markers, somatic mosaicism with partial haploid loss of 1p involving the RH locus was found to be responsible for the observed Rhc phenotype anomaly in both individuals studied, encompassing at least 26.7 and 42.4 Mb, respectively.
The high red cell expression of the antithetical C (RH2) antigen, nearly approaching levels of RHCE*C homozygous controls, indicates that the deletion of a part of 1p (eliminating the RHCE*C allele) has been repaired by a duplication of homologous stretches of the other chromosome harboring the RHCE*C allele. This view is further supported by the FISH results, showing the uniform presence of two RH loci in all examined cell nuclei. Accordingly, also LOH-affected cells did not show an RH deletion on their altered 1p that would be recognized by only one RH-FISH signal, as demonstrated previously.4 Instead, they appear to have retained RH loci on both 1p, not distinguishable from normal cells in this assay. The mechanism of the mixed-field agglutination in serological Rhc typing is, therefore, probably a somatic recombination with partial chromosome loss followed by a duplication.
Further studies designed to identify the cell lines and tissues that were affected by LOH revealed a differential configuration in the 2 propositae (see insert of Figure 3). In proposita B, LOH was observed in a lineage-specific distribution, occurring in a fraction of myeloid cell subsets but not in lymphoid compartments or non-hematopoietic tissues. Accordingly, only some, but not all, of the studied BFU-E colonies showed LOH. These results are compatible with the predominant genetic background of spontaneous Rh phenotype splitting as investigated in an earlier study.4 In the vast majority of individuals with mixed RhD and RhC or RhE phenotype, myeloid-lineage restricted mosaicism caused by LOH of variable chromosome 1 stretches encompassing the RHD/RHCE loci had been identified. In the present study, for the first time, this genetic background was documented with respect to spontaneous Rhc phenotype anomaly.
In contrast, proposita A showed a different spectrum of tissue involvement by LOH. Besides some of the myeloid stem cells and BFU-E colonies, also lymphocytes and hair roots were affected by this somatic change. These results indicate that LOH developed in a pluripotent stem cell line at an early stage of ontogenetic development, still capable of differentiating into hematopoietic as well as hair root cells. Such a constellation has not so far been described.
Copy-neutral LOH on 1p can compromise expression of many different genes, including those encoding Rh blood group antigens. The analysis of discrepant blood grouping results with mixed-field agglutination patterns is essential for safe transfusion therapy of such patients. Unequivocal blood group typing is a prerequisite for transfusion support and prenatal investigations evaluating fetomaternal incompatibility. At many institutions, not only ABO and RhD typing is performed, but also further highly immunogenic antigens including c, K and others are increasingly taken into account for transfusion matching. Such extended matching strategy was markedly shown to reduce the alloimmunization rate of transfusion recipients,28 an effect especially desirable for multi-transfused patient cohorts or women of childbearing age.3228 For both propositae, neither anti-c nor anti-C alloimmunization is to be expected, as both antigens are present. Hence, no particular transfusion strategy seems to be required regarding these two antigens.
Of note, mixed blood group phenotypes often escape serological detection but may be unveiled by molecular screening. The latter is of particular relevance for blood donor testing: it could have avoided a number of documented anti-D immunizations by red cell concentrates from serologically D-negative blood donors with an undetected D-positive cell subset.18
Apart from these implications for transfusion medicine, the blood group anomaly may only be the first evidence of an underlying genetic alteration of possibly extended clinical relevance. While it is increasingly recognized that somatic mosaicism including LOH may not be uncommon in apparently healthy subjects,3433 LOH-based blood group discrepancy may well represent a surrogate marker of myeloid diseases.363513114 Apart from acute myeloid leukemia and myelodysplastic syndrome,3837 allelic loss on 1p was also detected in many other malignancies, such as colorectal cancer, neuroblastoma, lung cancer and hepatocellular carcinoma.4239 Hence, this chromosomal region is probably home to tumor suppressor genes. It may be concluded that, depending on individual tissue distribution of LOH on 1p, the potential loss of tumor suppressor gene function could increase the risk for malignant transformation in affected organs. Alternatively, copy-neutral LOH may also result in duplication of oncogenic mutations with a subsequently increased likelihood of cancer.35 Recent data indicate that detection of LOH may not only have diagnostic but also prognostic potential for myeloid neoplasms.43376 Taken together, when encountering a patient with spontaneous blood group phenotype splitting, clinical and laboratory screening investigations for hematologic disease should be considered.
Footnotes
- Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/632
- Received July 5, 2018.
- Accepted September 20, 2018.
References
- Daniels G. Human blood groups. Wiley-Blackwell: Oxford; 2013. Google Scholar
- Flegel WA. Molecular genetics and clinical applications for RH. Transfus Apher Sci. 2011; 44(1):81-91. PubMedhttps://doi.org/10.1016/j.transci.2010.12.013Google Scholar
- Drexler C, Wagner T. Blood group chimerism. Curr Opin Hematol. 2006; 13(6):484-489. PubMedhttps://doi.org/10.1097/01.moh.0000245690.54956.f3Google Scholar
- Körmöczi GF, Dauber EM, Haas OA. Mosaicism due to myeloid lineage restricted loss of heterozygosity as cause of spontaneous Rh phenotype splitting. Blood. 2007; 110(6):2148-2157. PubMedhttps://doi.org/10.1182/blood-2007-01-068106Google Scholar
- Tovey GH, Lockyer JW, Tierney RB. Changes in Rh grouping reactions in a case of leukaemia. Vox Sang. 1961; 6(5):628-631. PubMedGoogle Scholar
- Orlando N, Putzulu R, Nuzzolo ER. Primary myelofibrosis: when the clone manifests with Rh phenotype splitting. Ann Hematol. 2014; 93(6):1077-1078. Google Scholar
- Majsky A. Some cases of leukaemia with modifications of the D(Rho)-receptor. Neoplasma. 1967; 14(4):335-344. PubMedGoogle Scholar
- Bracey AW, McGinniss MH, Levine RM, Whang-Peng J. Rh mosaicism and aberrant MNSs antigen expression in a patient with chronic myelogenous leukemia. Am J Clin Pathol. 1983; 79(3):397-401. PubMedhttps://doi.org/10.1093/ajcp/79.3.397Google Scholar
- Mertens G, Gielis M, Muylle L, de Raedt S. Loss of D and C expression in chronic myelomonocytic leukemia. Transfusion. 1997; 37(8):880-881. Google Scholar
- van Bockstaele DR, Berneman ZN, Muylle L, Cole-Dergent J, Peetermans ME. Flow cytometric analysis of erythrocytic D antigen density profile. Vox Sang. 1986; 51(1):40-46. PubMedGoogle Scholar
- Winters JL, Howard DS. Red blood cell antigen changes in malignancy: case report and review. Immunohematol. 2001; 17(1):1-9. PubMedGoogle Scholar
- Cooper B, Tishler PV, Atkins L, Breg WR. Loss of Rh antigen associated with acquired Rh antibodies and a chromosome translocation in a patient with myeloid metaplasia. Blood. 1979; 54(3):642-647. PubMedGoogle Scholar
- Mohandas K, Najfield V, Gilbert H, Azar P, Skerrett D. Loss and reappearance of Rho(D) antigen on the red blood cells of an individual with acute myelogenous leukemia. Immunohematol. 1994; 10(4):134-135. PubMedGoogle Scholar
- Callender ST, Kay HE, Lawler SD, Millard RE, Sanger R, Tippett PA. Two populations of Rh groups together with chromosomally abnormal cell lines in the bone marrow. Br Med J. 1971; 1(5741):131-133. PubMedhttps://doi.org/10.1136/bmj.1.5741.131Google Scholar
- Habibi B, Lopez M, Salmon C. Two new cases of Rh mosaicism - selective study of red cell populations. Vox Sang. 1974; 27(3):232-242. PubMedhttps://doi.org/10.1111/j.1423-0410.1974.tb02413.xGoogle Scholar
- Northoff H, Goldmann SF, Lattke H, Steinbach P. A patient, mosaic for Rh and Fy antigens lacking other signs of chimerism or chromosomal disorder. Vox Sang. 1984; 47(2):164-169. PubMedhttps://doi.org/10.1111/j.1423-0410.1984.tb01578.xGoogle Scholar
- Salaru NN, Lay WH. Rh blood group mosaicism in a healthy elderly woman. Vox Sang. 1985; 48(6):362-365. PubMedhttps://doi.org/10.1111/j.1423-0410.1985.tb00197.xGoogle Scholar
- Wagner FF, Frohmajer A, Flegel WA. RHD positive haplotypes in D negative Europeans. BMC Genet. 2001; 2:10. PubMedhttps://doi.org/10.1186/1471-2156-2-10Google Scholar
- Cherif-Zahar B, Bony V, Steffensen R. Shift from Rh-positive to Rh-negative phenotype caused by a somatic mutation within the RHD gene in a patient with chronic myelocytic leukaemia. Br J Haematol. 1998; 102(5):1263-1270. PubMedhttps://doi.org/10.1046/j.1365-2141.1998.00895.xGoogle Scholar
- Marsh WL, Chaganti RS, Gardner FH, Mayer K, Nowell PC, German J. Mapping human autosomes: evidence supporting assignment of rhesus to the short arm of chromosome No. 1. Science. 1974; 183(4128):966-968. PubMedhttps://doi.org/10.1126/science.183.4128.966Google Scholar
- Murdock A, Assip D, Hue-Roye K. RHD deletion in a patient with chronic myeloid leukemia. Immunohematology. 2008; 24(4):160-164. Google Scholar
- Körmöczi GF, Legler TJ, Daniels GL. Molecular and serologic characterization of DWI, a novel "high-grade" partial D. Transfusion. 2004; 44(4):575-580. Google Scholar
- Fritsch G, Witt V, Dubovsky J. Flow cytometric monitoring of hematopoietic reconstitution in myeloablated patients following allogeneic transplantation. Cytotherapy. 1999; 1(4):295-309. PubMedhttps://doi.org/10.1080/0032472031000141265Google Scholar
- Walsh PS, Metzger DA, Higuchi R. Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques. 1991; 10(4):506-513. PubMedGoogle Scholar
- Körmöczi GF, Förstemann E, Gabriel C, Mayr WR, Schönitzer D, Gassner C. Novel weak D types 31 and 32: adsorption-elution-supported D antigen analysis and comparison to prevalent weak D types. Transfusion. 2005; 45(10):1574-1580. Google Scholar
- Legler TJ, Lynen R, Maas JH. Prediction of fetal Rh D and Rh CcEe phenotype from maternal plasma with real-time polymerase chain reaction. Transfus Apher Sci. 2002; 27(3):217-223. PubMedhttps://doi.org/10.1016/S1473-0502(02)00068-XGoogle Scholar
- Tippett P. Blood group chimeras. A review. Vox Sang. 1983; 44(6):333-359. PubMedhttps://doi.org/10.1111/j.1423-0410.1983.tb03657.xGoogle Scholar
- Evers D, Middelburg RA, de Haas M. Red-blood-cell alloimmunisation in relation to antigens’ exposure and their immunogenicity: a cohort study. Lancet Haematol. 2016; 3(6):e284-292. Google Scholar
- Rees DC, Robinson S, Howard J. How I manage red cell transfusions in patients with sickle cell disease. Br J Haematol. 2018; 180(4):607-617. Google Scholar
- Körmöczi GF, Mayr WR. Responder individuality in red blood cell alloimmunization. Transfus Med Hemother. 2014; 41(6):446-451. Google Scholar
- Papay P, Hackner K, Vogelsang H. High risk of transfusion-induced alloimmunization of patients with inflammatory bowel disease. Am J Med. 2012; 125(7):717.e1-8. PubMedGoogle Scholar
- Delaney M, Wikman A, van de Watering L. Blood Group Antigen Matching Influence on Gestational Outcomes (AMIGO) study. Transfusion. 2017; 57(3):525-532. Google Scholar
- Machiela MJ, Chanock SJ. The ageing genome, clonal mosaicism and chronic disease. Curr Opin Genet Dev. 2017; 42(2):8-13. Google Scholar
- Forsberg LA, Gisselsson D, Dumanski JP. Mosaicism in health and disease - clones picking up speed. Nat Rev Genet. 2017; 18(2):128-142. Google Scholar
- Montemayor-Garcia C, Coward R, Albitar M. Acquired RhD mosaicism identifies fibrotic transformation of thrombopoietin receptor-mutated essential thrombocythemia. Transfusion. 2017; 57(9):2136-2139. Google Scholar
- Chow S, Pendergrast J, Ochoa-Garay G. Mixed fields on RhD typing as an indication of loss of heterozygosity on chromosome 1p in acute myeloid leukemia. Leuk Lymphoma. 2015; 56(7):2196-2199. Google Scholar
- O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. Blood. 2010; 115(14):2731-2739. PubMedhttps://doi.org/10.1182/blood-2009-10-201848Google Scholar
- Rumi E, Pietra D, Guglielmelli P. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood. 2013; 121(21):4388-4395. PubMedhttps://doi.org/10.1182/blood-2013-02-486050Google Scholar
- Zhou CZ, Qiu GQ, Zhang F, He L, Peng ZH. Loss of heterozygosity on chromosome 1 in sporadic colorectal carcinoma. World J Gastroenterol. 2004; 10(10):1431-1435. PubMedGoogle Scholar
- White PS, Maris JM, Beltinger C. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci USA. 1995; 92(12):5520-5524. PubMedhttps://doi.org/10.1073/pnas.92.12.5520Google Scholar
- Nomoto S, Haruki N, Tatematsu Y. Frequent allelic imbalance suggests involvement of a tumor suppressor gene at 1p36 in the pathogenesis of human lung cancers. Genes Chromosomes Cancer. 2000; 28(3):342-346. PubMedhttps://doi.org/10.1002/1098-2264(200007)28:3<342::AID-GCC13>3.0.CO;2-AGoogle Scholar
- Yeh SH, Chen PJ, Chen HL, Lai MY, Wang CC, Chen DS. Frequent genetic alterations at the distal region of chromosome 1p in human hepatocellular carcinomas. Cancer Res. 1994; 54(15):4188-4192. PubMedGoogle Scholar
- Gronseth CM, McElhone SE, Storer BE. Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia. Cancer. 2015; 121(17):2900-2908. PubMedhttps://doi.org/10.1002/cncr.29475Google Scholar