Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis
B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains d...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Ferrata Storti Foundation
2019
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| _version_ | 1797061306087374848 |
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| author | Agraz-Doblas, A Bueno, C Bashford-Rogers, R Roy, A Schneider, P Bardini, M Ballerini, P Cazzaniga, G Moreno, T Revilla, C Gut, M Valsecchi, MG Roberts, I Pieters, R De Lorenzo, P Varela, I Menendez, P Stam, RW |
| author_facet | Agraz-Doblas, A Bueno, C Bashford-Rogers, R Roy, A Schneider, P Bardini, M Ballerini, P Cazzaniga, G Moreno, T Revilla, C Gut, M Valsecchi, MG Roberts, I Pieters, R De Lorenzo, P Varela, I Menendez, P Stam, RW |
| author_sort | Agraz-Doblas, A |
| collection | OXFORD |
| description | B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, a multi-layered genome-wide analyses and validation was performed on a total of 124 de novo infant B-cell acute lymphoblastic leukemias uniformly diagnosed/treated according to Interfant99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in K- and N-RAS, and were subclonal and frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11)+ infant B-cell acute lymphoblastic leukemia, and RNA-sequencing showed transcriptomic similarities between t(4;11)+ infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem/progenitor cells, confirming a pre-VDJ fetal cellular origin for both t(4;11) and RASmut. The reciprocal fusion AF4-MLL was expressed in only 45% (19/43) of the t(4;11)+ patients, and HOXA cluster genes are exclusively expressed in AF4-MLL-expressing patients. Importantly, AF4-MLL/HOXA-expressing patients had a significantly better 4-year event-free survival (62.4% vs 11.7%, p=0.001), and overall-survival (73.7 versus 25.2%, p=0.016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to Interfant-06 protocol based on age at diagnosis, WBC count and Prednisone response. This study has clinical implications in disease outcome and diagnostic risk-stratification of t(4;11)+ infant B-cell acute lymphoblastic leukemia. |
| first_indexed | 2024-03-06T20:29:12Z |
| format | Journal article |
| id | oxford-uuid:307b649d-52b6-4ca1-847a-eab09645a4ef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:29:12Z |
| publishDate | 2019 |
| publisher | Ferrata Storti Foundation |
| record_format | dspace |
| spelling | oxford-uuid:307b649d-52b6-4ca1-847a-eab09645a4ef2022-03-26T13:01:41ZUnravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:307b649d-52b6-4ca1-847a-eab09645a4efEnglishSymplectic Elements at OxfordFerrata Storti Foundation2019Agraz-Doblas, ABueno, CBashford-Rogers, RRoy, ASchneider, PBardini, MBallerini, PCazzaniga, GMoreno, TRevilla, CGut, MValsecchi, MGRoberts, IPieters, RDe Lorenzo, PVarela, IMenendez, PStam, RWB-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, a multi-layered genome-wide analyses and validation was performed on a total of 124 de novo infant B-cell acute lymphoblastic leukemias uniformly diagnosed/treated according to Interfant99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in K- and N-RAS, and were subclonal and frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11)+ infant B-cell acute lymphoblastic leukemia, and RNA-sequencing showed transcriptomic similarities between t(4;11)+ infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem/progenitor cells, confirming a pre-VDJ fetal cellular origin for both t(4;11) and RASmut. The reciprocal fusion AF4-MLL was expressed in only 45% (19/43) of the t(4;11)+ patients, and HOXA cluster genes are exclusively expressed in AF4-MLL-expressing patients. Importantly, AF4-MLL/HOXA-expressing patients had a significantly better 4-year event-free survival (62.4% vs 11.7%, p=0.001), and overall-survival (73.7 versus 25.2%, p=0.016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to Interfant-06 protocol based on age at diagnosis, WBC count and Prednisone response. This study has clinical implications in disease outcome and diagnostic risk-stratification of t(4;11)+ infant B-cell acute lymphoblastic leukemia. |
| spellingShingle | Agraz-Doblas, A Bueno, C Bashford-Rogers, R Roy, A Schneider, P Bardini, M Ballerini, P Cazzaniga, G Moreno, T Revilla, C Gut, M Valsecchi, MG Roberts, I Pieters, R De Lorenzo, P Varela, I Menendez, P Stam, RW Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title | Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title_full | Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title_fullStr | Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title_full_unstemmed | Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title_short | Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
| title_sort | unravelling the cellular origin and clinical prognostic markers of infant b cell acute lymphoblastic leukemia using genome wide analysis |
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