GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.
Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Society of Hematology
2013
|
| _version_ | 1826302162788941824 |
|---|---|
| author | Roberts, I Alford, K Hall, G Juban, G Richmond, H Norton, A Vallance, G Perkins, K Marchi, E McGowan, S Roy, A Cowan, G Anthony, M Gupta, A Ho, J Uthaya, S Curley, A Rasiah, S Watts, T Nicholl, R Bedford-Russell, A Blumberg, R Thomas, A Gibson, B Halsey, C Lee, P Godambe, S Sweeney, C Bhatnagar, N Goriely, A Campbell, P Vyas, P |
| author_facet | Roberts, I Alford, K Hall, G Juban, G Richmond, H Norton, A Vallance, G Perkins, K Marchi, E McGowan, S Roy, A Cowan, G Anthony, M Gupta, A Ho, J Uthaya, S Curley, A Rasiah, S Watts, T Nicholl, R Bedford-Russell, A Blumberg, R Thomas, A Gibson, B Halsey, C Lee, P Godambe, S Sweeney, C Bhatnagar, N Goriely, A Campbell, P Vyas, P |
| author_sort | Roberts, I |
| collection | OXFORD |
| description | Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones. |
| first_indexed | 2024-03-07T05:43:22Z |
| format | Journal article |
| id | oxford-uuid:e65d5fdd-bc71-48a3-a4b7-11dc949891a7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:43:22Z |
| publishDate | 2013 |
| publisher | American Society of Hematology |
| record_format | dspace |
| spelling | oxford-uuid:e65d5fdd-bc71-48a3-a4b7-11dc949891a72022-03-27T10:30:37ZGATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e65d5fdd-bc71-48a3-a4b7-11dc949891a7EnglishSymplectic Elements at OxfordAmerican Society of Hematology2013Roberts, IAlford, KHall, GJuban, GRichmond, HNorton, AVallance, GPerkins, KMarchi, EMcGowan, SRoy, ACowan, GAnthony, MGupta, AHo, JUthaya, SCurley, ARasiah, SWatts, TNicholl, RBedford-Russell, ABlumberg, RThomas, AGibson, BHalsey, CLee, PGodambe, SSweeney, CBhatnagar, NGoriely, ACampbell, PVyas, PTransient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones. |
| spellingShingle | Roberts, I Alford, K Hall, G Juban, G Richmond, H Norton, A Vallance, G Perkins, K Marchi, E McGowan, S Roy, A Cowan, G Anthony, M Gupta, A Ho, J Uthaya, S Curley, A Rasiah, S Watts, T Nicholl, R Bedford-Russell, A Blumberg, R Thomas, A Gibson, B Halsey, C Lee, P Godambe, S Sweeney, C Bhatnagar, N Goriely, A Campbell, P Vyas, P GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title | GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title_full | GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title_fullStr | GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title_full_unstemmed | GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title_short | GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. |
| title_sort | gata1 mutant clones are frequent and often unsuspected in babies with down syndrome identification of a population at risk of leukemia |
| work_keys_str_mv | AT robertsi gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT alfordk gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT hallg gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT jubang gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT richmondh gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT nortona gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT vallanceg gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT perkinsk gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT marchie gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT mcgowans gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT roya gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT cowang gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT anthonym gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT guptaa gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT hoj gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT uthayas gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT curleya gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT rasiahs gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT wattst gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT nichollr gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT bedfordrussella gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT blumbergr gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT thomasa gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT gibsonb gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT halseyc gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT leep gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT godambes gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT sweeneyc gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT bhatnagarn gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT gorielya gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT campbellp gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia AT vyasp gata1mutantclonesarefrequentandoftenunsuspectedinbabieswithdownsyndromeidentificationofapopulationatriskofleukemia |