ena-STUDY-UNIVERSIDAD DE CANTABRIA-23-11-2017-10:29:18:813-92
The mutational and transcriptome landscape of infant B-cell acute lymphoblastic leukemia: The INTERFANT treatment protocol experience
Infant B-cell precursor acute lymphoblastic leukemia (iBCP-ALL) has a poor prognosis, especially with MLL-gene rearrangements (MLLr), which occur in ~80% of the patients. MLLr are clonal leukemogenic drivers that might initiate leukemia without additional genetic lesions. It is however challenging to reproduce MLLr-mediated iBCP-ALL in murine/humanized models and, consequently, key aspects of MLLr iBCP-ALL pathogenesis remain enigmatic. Here, we performed whole-genome, exome and RNA sequencing on an Interfant study discovery cohort of 42 iBCP-ALLs (27 MLL-AF4+, 5 MLL-AF9+ and 10 non-MLL). An independent validation cohort of 82 iBCP-ALLs (43 MLL-AF4+, 11 MLL-AF9+, and 28 non-MLL) was used for targeted DNA sequencing and qRT-PCR. We found that iBCP-ALL, irrespective of the presence/subtype of MLLr shows an extremely low frequency of somatic mutations, with the predominant leukemic clone carrying a mean of 2,5 (range:0-10) non-silent mutations. Recurrent mutations were exclusively found in KRAS and NRAS, which were more frequent in the MLL-AF4+ (42%) than in MLL-AF9+/non-MLL (19%-25%) iBCP-ALL subgroups due to common NRAS mutations found in MLL-AF4+ infants (32% vs 6%; p<0.01). These mutations were subclonal and frequently lost at relapse, despite a larger number of non-silent but not-recurrent mutations (19.5 mutations/patient, range:1-434). RNA-sequencing and qRT-PCR validation unravelled that HOXA cluster genes were only expressed in t(4;11)+ patients expressing the reciprocal fusion AF4-MLL. Importantly, AF4-MLL/HOXA-expressing patients displayed a better clinical outcome. Thus, iBCP-ALL shows a silent mutational landscape regardless the status of MLL, and the expression of AF4-MLL defines a subgroup of t(4;11)+ iBCP-ALL with better prognosis and specific upregulation of HOXA cluster genes.
Infant B-cell precursor acute lymphoblastic leukemia (iBCP-ALL) has a poor prognosis, especially with MLL-gene rearrangements (MLLr), which occur in ~80% of the patients. MLLr are clonal leukemogenic drivers that might initiate leukemia without additional genetic lesions. It is however challenging to reproduce MLLr-mediated iBCP-ALL in murine/humanized models and, consequently, key aspects of MLLr iBCP-ALL pathogenesis remain enigmatic. Here, we performed whole-genome, exome and RNA sequencing on an Interfant study discovery cohort of 42 iBCP-ALLs (27 MLL-AF4+, 5 MLL-AF9+ and 10 non-MLL). An independent validation cohort of 82 iBCP-ALLs (43 MLL-AF4+, 11 MLL-AF9+, and 28 non-MLL) was used for targeted DNA sequencing and qRT-PCR. We found that iBCP-ALL, irrespective of the presence/subtype of MLLr shows an extremely low frequency of somatic mutations, with the predominant leukemic clone carrying a mean of 2,5 (range:0-10) non-silent mutations. Recurrent mutations were exclusively found in KRAS and NRAS, which were more frequent in the MLL-AF4+ (42%) than in MLL-AF9+/non-MLL (19%-25%) iBCP-ALL subgroups due to common NRAS mutations found in MLL-AF4+ infants (32% vs 6%; p<0.01). These mutations were subclonal and frequently lost at relapse, despite a larger number of non-silent but not-recurrent mutations (19.5 mutations/patient, range:1-434). RNA-sequencing and qRT-PCR validation unravelled that HOXA cluster genes were only expressed in t(4;11)+ patients expressing the reciprocal fusion AF4-MLL. Importantly, AF4-MLL/HOXA-expressing patients displayed a better clinical outcome. Thus, iBCP-ALL shows a silent mutational landscape regardless the status of MLL, and the expression of AF4-MLL defines a subgroup of t(4;11)+ iBCP-ALL with better prognosis and specific upregulation of HOXA cluster genes.