Eintrag weiter verarbeiten
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome
Gespeichert in:
| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , |
| In: | Blood, 124, 2014, 21, S. 2349-2349 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene |
|---|---|
| author |
Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene |
| spellingShingle |
Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene Blood Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome Cell Biology Hematology Immunology Biochemistry |
| author_sort |
bhatnagar, neha |
| spelling |
Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v124.21.2349.2349 <jats:title>Abstract</jats:title> <jats:p>Children with Down syndrome (DS; trisomy 21) have an increased risk of acute myeloid leukemia (ML-DS) in the first 5 years of life. In most cases ML-DS is preceded by Transient Abnormal Myelopoiesis (TAM), a fetal/neonatal pre-leukemic disorder unique to DS which regresses after birth. Both TAM and ML-DS harbor acquired N-terminal mutations in the hematopoietic transcription factor gene GATA1. In a prospective study of 200 DS neonates, we recently showed that 29% had acquired GATA1 mutations including 17/200 (8.5%) with clinical or hematologic evidence of TAM; the remaining 20.5% were clinically and hematologically 'silent', with smaller mutant GATA1 clones and lower blast frequency compared to overt TAM. The reasons why some DS neonates develop overt TAM and the factors which determine mutant GATA1 clone size are unknown. To address this, we analysed data from neonates in the prospective Oxford-Imperial DS Cohort Study and investigated the impact of 30 clinical and hematologic factors on clone size using statistical and mathematical modelling. Mutant GATA1 clones were determined in 54 neonates by targeted next generation sequencing of GATA1 exon 2 (mutation detection limit 0.3%). Clone size was determined by analysing original unprocessed reads using less stringent filtering parameters and counting reads containing mutated v total sequence. Correlation analysis identified 4 hematologic variables correlated with mutant GATA1 clone size: circulating nucleated red cells (r=+0.5003; p=0.0001), platelets (r=+0.436; p=0.001), total leukocytes (r=+0.7094; p<0.001) and % blasts (r=+0.7292; p<0.001); clone size was higher in neonates with megakaryocyte fragments (p=0.0024) and platelets >150x109/L (p=0.019). Numbers of neutrophils, monocytes, basophils, eosinophils and lymphocytes did not correlate with GATA1 clone size. Clinical variables significantly correlated with clone size were hepatomegaly (p=0.0016), splenomegaly (p=0.0001) and rash (0.0174). The only pregnancy-related variables affecting mutant GATA1 clone size were intrauterine growth restriction and maternal diabetes (p=0.0156). Linear regression to determine the joint impact of all 30 variables on clone size (r2=0.88) followed by Lasso penalization identified the same 4 hematologic variables (nucleated red cells, platelets, total leukocytes and % blasts); Lasso penalized regression with these 4 variables gave a coefficient of determination of 0.63. Together these data suggest that chronic intrauterine hypoxia may affect expansion/differentiation of mutant GATA1 clones in DS. Consistent with this, nucleated red cells from 3 neonates with TAM all harbored GATA1 mutations identical to those in total circulating nucleated cells. Since neither perinatal infection nor gestational age at birth correlated with mutant GATA1 clone size, infection-related cytokines and the timing of acquisition of a mutant GATA1 clone during fetal development may not play a major role in determining clone size. Finally, a hierarchical model to investigate the impact of GATA1 mutation on hematopoietic stem and progenitor (HSPC) differentiation in DS neonates using a Bayesian approach also predicted increased erythroid cell output from GATA1 mutated HSPC v HSPC without a GATA1 mutation. In conclusion, in neonates with DS the size of the mutant GATA1 clone correlates with the presence of clinical signs of hepatomegaly, splenomegaly and skin rash; mutant GATA1 clone size correlates with the numbers of circulating nucleated red cells, platelets and blast cells suggesting that GATA1 mutant HSPC retain the ability to differentiate down the erythroid and megakaryocyte lineage; intrauterine hypoxia may be one of the factors driving expansion and/or maturation of the GATA1 mutant clone during fetal life in DS.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome Blood |
| doi_str_mv |
10.1182/blood.v124.21.2349.2349 |
| facet_avail |
Online Free |
| finc_class_facet |
Biologie Medizin Chemie und Pharmazie |
| format |
ElectronicArticle |
| fullrecord |
blob:ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI0LjIxLjIzNDkuMjM0OQ |
| id |
ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI0LjIxLjIzNDkuMjM0OQ |
| institution |
DE-Gla1 DE-Zi4 DE-15 DE-Pl11 DE-Rs1 DE-105 DE-14 DE-Ch1 DE-L229 DE-D275 DE-Bn3 DE-Brt1 DE-Zwi2 DE-D161 |
| imprint |
American Society of Hematology, 2014 |
| imprint_str_mv |
American Society of Hematology, 2014 |
| issn |
0006-4971 1528-0020 |
| issn_str_mv |
0006-4971 1528-0020 |
| language |
English |
| mega_collection |
American Society of Hematology (CrossRef) |
| match_str |
bhatnagar2014clinicalandhematologicimpactoffetalandperinatalvariablesonmutantgata1clonesizeinneonateswithdownsyndrome |
| publishDateSort |
2014 |
| publisher |
American Society of Hematology |
| recordtype |
ai |
| record_format |
ai |
| series |
Blood |
| source_id |
49 |
| title |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_unstemmed |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_full |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_fullStr |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_full_unstemmed |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_short |
Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_sort |
clinical and hematologic impact of fetal and perinatal variables on mutant gata1 clone size in neonates with down syndrome |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v124.21.2349.2349 |
| publishDate |
2014 |
| physical |
2349-2349 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Children with Down syndrome (DS; trisomy 21) have an increased risk of acute myeloid leukemia (ML-DS) in the first 5 years of life. In most cases ML-DS is preceded by Transient Abnormal Myelopoiesis (TAM), a fetal/neonatal pre-leukemic disorder unique to DS which regresses after birth. Both TAM and ML-DS harbor acquired N-terminal mutations in the hematopoietic transcription factor gene GATA1. In a prospective study of 200 DS neonates, we recently showed that 29% had acquired GATA1 mutations including 17/200 (8.5%) with clinical or hematologic evidence of TAM; the remaining 20.5% were clinically and hematologically 'silent', with smaller mutant GATA1 clones and lower blast frequency compared to overt TAM. The reasons why some DS neonates develop overt TAM and the factors which determine mutant GATA1 clone size are unknown. To address this, we analysed data from neonates in the prospective Oxford-Imperial DS Cohort Study and investigated the impact of 30 clinical and hematologic factors on clone size using statistical and mathematical modelling. Mutant GATA1 clones were determined in 54 neonates by targeted next generation sequencing of GATA1 exon 2 (mutation detection limit 0.3%). Clone size was determined by analysing original unprocessed reads using less stringent filtering parameters and counting reads containing mutated v total sequence. Correlation analysis identified 4 hematologic variables correlated with mutant GATA1 clone size: circulating nucleated red cells (r=+0.5003; p=0.0001), platelets (r=+0.436; p=0.001), total leukocytes (r=+0.7094; p<0.001) and % blasts (r=+0.7292; p<0.001); clone size was higher in neonates with megakaryocyte fragments (p=0.0024) and platelets >150x109/L (p=0.019). Numbers of neutrophils, monocytes, basophils, eosinophils and lymphocytes did not correlate with GATA1 clone size. Clinical variables significantly correlated with clone size were hepatomegaly (p=0.0016), splenomegaly (p=0.0001) and rash (0.0174). The only pregnancy-related variables affecting mutant GATA1 clone size were intrauterine growth restriction and maternal diabetes (p=0.0156). Linear regression to determine the joint impact of all 30 variables on clone size (r2=0.88) followed by Lasso penalization identified the same 4 hematologic variables (nucleated red cells, platelets, total leukocytes and % blasts); Lasso penalized regression with these 4 variables gave a coefficient of determination of 0.63. Together these data suggest that chronic intrauterine hypoxia may affect expansion/differentiation of mutant GATA1 clones in DS. Consistent with this, nucleated red cells from 3 neonates with TAM all harbored GATA1 mutations identical to those in total circulating nucleated cells. Since neither perinatal infection nor gestational age at birth correlated with mutant GATA1 clone size, infection-related cytokines and the timing of acquisition of a mutant GATA1 clone during fetal development may not play a major role in determining clone size. Finally, a hierarchical model to investigate the impact of GATA1 mutation on hematopoietic stem and progenitor (HSPC) differentiation in DS neonates using a Bayesian approach also predicted increased erythroid cell output from GATA1 mutated HSPC v HSPC without a GATA1 mutation. In conclusion, in neonates with DS the size of the mutant GATA1 clone correlates with the presence of clinical signs of hepatomegaly, splenomegaly and skin rash; mutant GATA1 clone size correlates with the numbers of circulating nucleated red cells, platelets and blast cells suggesting that GATA1 mutant HSPC retain the ability to differentiate down the erythroid and megakaryocyte lineage; intrauterine hypoxia may be one of the factors driving expansion and/or maturation of the GATA1 mutant clone during fetal life in DS.</jats:p>
<jats:sec>
<jats:title>Disclosures</jats:title>
<jats:p>No relevant conflicts of interest to declare.</jats:p>
</jats:sec> |
| container_issue |
21 |
| container_start_page |
2349 |
| container_title |
Blood |
| container_volume |
124 |
| format_de105 |
Article, E-Article |
| format_de14 |
Article, E-Article |
| format_de15 |
Article, E-Article |
| format_de520 |
Article, E-Article |
| format_de540 |
Article, E-Article |
| format_dech1 |
Article, E-Article |
| format_ded117 |
Article, E-Article |
| format_degla1 |
E-Article |
| format_del152 |
Buch |
| format_del189 |
Article, E-Article |
| format_dezi4 |
Article |
| format_dezwi2 |
Article, E-Article |
| format_finc |
Article, E-Article |
| format_nrw |
Article, E-Article |
| _version_ |
1792322736177020937 |
| geogr_code |
not assigned |
| last_indexed |
2024-03-01T11:22:32.429Z |
| geogr_code_person |
not assigned |
| openURL |
url_ver=Z39.88-2004&ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fvufind.svn.sourceforge.net%3Agenerator&rft.title=Clinical+and+Hematologic+Impact+of+Fetal+and+Perinatal+Variables+on+Mutant+GATA1+Clone+Size+in+Neonates+with+Down+Syndrome&rft.date=2014-12-06&genre=article&issn=1528-0020&volume=124&issue=21&spage=2349&epage=2349&pages=2349-2349&jtitle=Blood&atitle=Clinical+and+Hematologic+Impact+of+Fetal+and+Perinatal+Variables+on+Mutant+GATA1+Clone+Size+in+Neonates+with+Down+Syndrome&aulast=Roberts&aufirst=Irene&rft_id=info%3Adoi%2F10.1182%2Fblood.v124.21.2349.2349&rft.language%5B0%5D=eng |
| SOLR | |
| _version_ | 1792322736177020937 |
| author | Bhatnagar, Neha, Perkins, Kelly, Filippi, Sarah, Richmond, Helen, Bonnici, Joanna, Alford, Kate, Hall, Georgina, Juban, Gaëtan, McGowan, Simon, Roy, Anindita, Elliott, Natalina, Stumpf, Michael, Norton, Alice, Vyas, Paresh, Roberts, Irene |
| author_facet | Bhatnagar, Neha, Perkins, Kelly, Filippi, Sarah, Richmond, Helen, Bonnici, Joanna, Alford, Kate, Hall, Georgina, Juban, Gaëtan, McGowan, Simon, Roy, Anindita, Elliott, Natalina, Stumpf, Michael, Norton, Alice, Vyas, Paresh, Roberts, Irene, Bhatnagar, Neha, Perkins, Kelly, Filippi, Sarah, Richmond, Helen, Bonnici, Joanna, Alford, Kate, Hall, Georgina, Juban, Gaëtan, McGowan, Simon, Roy, Anindita, Elliott, Natalina, Stumpf, Michael, Norton, Alice, Vyas, Paresh, Roberts, Irene |
| author_sort | bhatnagar, neha |
| container_issue | 21 |
| container_start_page | 2349 |
| container_title | Blood |
| container_volume | 124 |
| description | <jats:title>Abstract</jats:title> <jats:p>Children with Down syndrome (DS; trisomy 21) have an increased risk of acute myeloid leukemia (ML-DS) in the first 5 years of life. In most cases ML-DS is preceded by Transient Abnormal Myelopoiesis (TAM), a fetal/neonatal pre-leukemic disorder unique to DS which regresses after birth. Both TAM and ML-DS harbor acquired N-terminal mutations in the hematopoietic transcription factor gene GATA1. In a prospective study of 200 DS neonates, we recently showed that 29% had acquired GATA1 mutations including 17/200 (8.5%) with clinical or hematologic evidence of TAM; the remaining 20.5% were clinically and hematologically 'silent', with smaller mutant GATA1 clones and lower blast frequency compared to overt TAM. The reasons why some DS neonates develop overt TAM and the factors which determine mutant GATA1 clone size are unknown. To address this, we analysed data from neonates in the prospective Oxford-Imperial DS Cohort Study and investigated the impact of 30 clinical and hematologic factors on clone size using statistical and mathematical modelling. Mutant GATA1 clones were determined in 54 neonates by targeted next generation sequencing of GATA1 exon 2 (mutation detection limit 0.3%). Clone size was determined by analysing original unprocessed reads using less stringent filtering parameters and counting reads containing mutated v total sequence. Correlation analysis identified 4 hematologic variables correlated with mutant GATA1 clone size: circulating nucleated red cells (r=+0.5003; p=0.0001), platelets (r=+0.436; p=0.001), total leukocytes (r=+0.7094; p<0.001) and % blasts (r=+0.7292; p<0.001); clone size was higher in neonates with megakaryocyte fragments (p=0.0024) and platelets >150x109/L (p=0.019). Numbers of neutrophils, monocytes, basophils, eosinophils and lymphocytes did not correlate with GATA1 clone size. Clinical variables significantly correlated with clone size were hepatomegaly (p=0.0016), splenomegaly (p=0.0001) and rash (0.0174). The only pregnancy-related variables affecting mutant GATA1 clone size were intrauterine growth restriction and maternal diabetes (p=0.0156). Linear regression to determine the joint impact of all 30 variables on clone size (r2=0.88) followed by Lasso penalization identified the same 4 hematologic variables (nucleated red cells, platelets, total leukocytes and % blasts); Lasso penalized regression with these 4 variables gave a coefficient of determination of 0.63. Together these data suggest that chronic intrauterine hypoxia may affect expansion/differentiation of mutant GATA1 clones in DS. Consistent with this, nucleated red cells from 3 neonates with TAM all harbored GATA1 mutations identical to those in total circulating nucleated cells. Since neither perinatal infection nor gestational age at birth correlated with mutant GATA1 clone size, infection-related cytokines and the timing of acquisition of a mutant GATA1 clone during fetal development may not play a major role in determining clone size. Finally, a hierarchical model to investigate the impact of GATA1 mutation on hematopoietic stem and progenitor (HSPC) differentiation in DS neonates using a Bayesian approach also predicted increased erythroid cell output from GATA1 mutated HSPC v HSPC without a GATA1 mutation. In conclusion, in neonates with DS the size of the mutant GATA1 clone correlates with the presence of clinical signs of hepatomegaly, splenomegaly and skin rash; mutant GATA1 clone size correlates with the numbers of circulating nucleated red cells, platelets and blast cells suggesting that GATA1 mutant HSPC retain the ability to differentiate down the erythroid and megakaryocyte lineage; intrauterine hypoxia may be one of the factors driving expansion and/or maturation of the GATA1 mutant clone during fetal life in DS.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> |
| doi_str_mv | 10.1182/blood.v124.21.2349.2349 |
| facet_avail | Online, Free |
| finc_class_facet | Biologie, Medizin, Chemie und Pharmazie |
| format | ElectronicArticle |
| format_de105 | Article, E-Article |
| format_de14 | Article, E-Article |
| format_de15 | Article, E-Article |
| format_de520 | Article, E-Article |
| format_de540 | Article, E-Article |
| format_dech1 | Article, E-Article |
| format_ded117 | Article, E-Article |
| format_degla1 | E-Article |
| format_del152 | Buch |
| format_del189 | Article, E-Article |
| format_dezi4 | Article |
| format_dezwi2 | Article, E-Article |
| format_finc | Article, E-Article |
| format_nrw | Article, E-Article |
| geogr_code | not assigned |
| geogr_code_person | not assigned |
| id | ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI0LjIxLjIzNDkuMjM0OQ |
| imprint | American Society of Hematology, 2014 |
| imprint_str_mv | American Society of Hematology, 2014 |
| institution | DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161 |
| issn | 0006-4971, 1528-0020 |
| issn_str_mv | 0006-4971, 1528-0020 |
| language | English |
| last_indexed | 2024-03-01T11:22:32.429Z |
| match_str | bhatnagar2014clinicalandhematologicimpactoffetalandperinatalvariablesonmutantgata1clonesizeinneonateswithdownsyndrome |
| mega_collection | American Society of Hematology (CrossRef) |
| physical | 2349-2349 |
| publishDate | 2014 |
| publishDateSort | 2014 |
| publisher | American Society of Hematology |
| record_format | ai |
| recordtype | ai |
| series | Blood |
| source_id | 49 |
| spelling | Bhatnagar, Neha Perkins, Kelly Filippi, Sarah Richmond, Helen Bonnici, Joanna Alford, Kate Hall, Georgina Juban, Gaëtan McGowan, Simon Roy, Anindita Elliott, Natalina Stumpf, Michael Norton, Alice Vyas, Paresh Roberts, Irene 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v124.21.2349.2349 <jats:title>Abstract</jats:title> <jats:p>Children with Down syndrome (DS; trisomy 21) have an increased risk of acute myeloid leukemia (ML-DS) in the first 5 years of life. In most cases ML-DS is preceded by Transient Abnormal Myelopoiesis (TAM), a fetal/neonatal pre-leukemic disorder unique to DS which regresses after birth. Both TAM and ML-DS harbor acquired N-terminal mutations in the hematopoietic transcription factor gene GATA1. In a prospective study of 200 DS neonates, we recently showed that 29% had acquired GATA1 mutations including 17/200 (8.5%) with clinical or hematologic evidence of TAM; the remaining 20.5% were clinically and hematologically 'silent', with smaller mutant GATA1 clones and lower blast frequency compared to overt TAM. The reasons why some DS neonates develop overt TAM and the factors which determine mutant GATA1 clone size are unknown. To address this, we analysed data from neonates in the prospective Oxford-Imperial DS Cohort Study and investigated the impact of 30 clinical and hematologic factors on clone size using statistical and mathematical modelling. Mutant GATA1 clones were determined in 54 neonates by targeted next generation sequencing of GATA1 exon 2 (mutation detection limit 0.3%). Clone size was determined by analysing original unprocessed reads using less stringent filtering parameters and counting reads containing mutated v total sequence. Correlation analysis identified 4 hematologic variables correlated with mutant GATA1 clone size: circulating nucleated red cells (r=+0.5003; p=0.0001), platelets (r=+0.436; p=0.001), total leukocytes (r=+0.7094; p<0.001) and % blasts (r=+0.7292; p<0.001); clone size was higher in neonates with megakaryocyte fragments (p=0.0024) and platelets >150x109/L (p=0.019). Numbers of neutrophils, monocytes, basophils, eosinophils and lymphocytes did not correlate with GATA1 clone size. Clinical variables significantly correlated with clone size were hepatomegaly (p=0.0016), splenomegaly (p=0.0001) and rash (0.0174). The only pregnancy-related variables affecting mutant GATA1 clone size were intrauterine growth restriction and maternal diabetes (p=0.0156). Linear regression to determine the joint impact of all 30 variables on clone size (r2=0.88) followed by Lasso penalization identified the same 4 hematologic variables (nucleated red cells, platelets, total leukocytes and % blasts); Lasso penalized regression with these 4 variables gave a coefficient of determination of 0.63. Together these data suggest that chronic intrauterine hypoxia may affect expansion/differentiation of mutant GATA1 clones in DS. Consistent with this, nucleated red cells from 3 neonates with TAM all harbored GATA1 mutations identical to those in total circulating nucleated cells. Since neither perinatal infection nor gestational age at birth correlated with mutant GATA1 clone size, infection-related cytokines and the timing of acquisition of a mutant GATA1 clone during fetal development may not play a major role in determining clone size. Finally, a hierarchical model to investigate the impact of GATA1 mutation on hematopoietic stem and progenitor (HSPC) differentiation in DS neonates using a Bayesian approach also predicted increased erythroid cell output from GATA1 mutated HSPC v HSPC without a GATA1 mutation. In conclusion, in neonates with DS the size of the mutant GATA1 clone correlates with the presence of clinical signs of hepatomegaly, splenomegaly and skin rash; mutant GATA1 clone size correlates with the numbers of circulating nucleated red cells, platelets and blast cells suggesting that GATA1 mutant HSPC retain the ability to differentiate down the erythroid and megakaryocyte lineage; intrauterine hypoxia may be one of the factors driving expansion and/or maturation of the GATA1 mutant clone during fetal life in DS.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome Blood |
| spellingShingle | Bhatnagar, Neha, Perkins, Kelly, Filippi, Sarah, Richmond, Helen, Bonnici, Joanna, Alford, Kate, Hall, Georgina, Juban, Gaëtan, McGowan, Simon, Roy, Anindita, Elliott, Natalina, Stumpf, Michael, Norton, Alice, Vyas, Paresh, Roberts, Irene, Blood, Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome, Cell Biology, Hematology, Immunology, Biochemistry |
| title | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_full | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_fullStr | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_full_unstemmed | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_short | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| title_sort | clinical and hematologic impact of fetal and perinatal variables on mutant gata1 clone size in neonates with down syndrome |
| title_unstemmed | Clinical and Hematologic Impact of Fetal and Perinatal Variables on Mutant GATA1 Clone Size in Neonates with Down Syndrome |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v124.21.2349.2349 |