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

Agraz-Doblas, A., Bueno, C., Bashford-Rogers, R., Roy, A., Schneider, P., Bardini, M., et al. (2019). Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis. HAEMATOLOGICA, 104(6), 1176-1188 [10.3324/haematol.2018.206375].

Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

Bardini, Michela
Membro del Collaboration Group
;
Cazzaniga, Gianni;Valsecchi, Maria G
Membro del Collaboration Group
;
2019

Abstract

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
Articolo in rivista - Articolo scientifico
Leukemic Stem Cell; Lymphocytes; Pediatric Acute Lymphoblastic Leukemia
English
20-dic-2018
2019
104
6
1176
1188
open
Agraz-Doblas, A., Bueno, C., Bashford-Rogers, R., Roy, A., Schneider, P., Bardini, M., et al. (2019). Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis. HAEMATOLOGICA, 104(6), 1176-1188 [10.3324/haematol.2018.206375].
File in questo prodotto:
File Dimensione Formato  
Agraz-Doblas_infant.pdf

accesso aperto

Tipologia di allegato: Publisher’s Version (Version of Record, VoR)
Dimensione 2.88 MB
Formato Adobe PDF
2.88 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/226322
Citazioni
  • Scopus 71
  • ???jsp.display-item.citation.isi??? 69
Social impact