Distinctive Genotypes In Infants With T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Authors: Mansur Marcela B , Van Delft Frederik W , Furness Caroline L , Emerenciano Mariana , Colman Susan M , Butcher Emma , Kempski Helena , Clappier Emmanuelle , Cave Hélène , Soulier Jean , Pombo-de-Oliveira Maria S. , Greaves Mel , Ford Anthony M 
Published: October 2019

Abstract
Acute Lymphoblastic Leukaemia (ALL) in children is a disease strongly categorised by age at diagnosis of overt disease, leukaemic subtype and recurrent genetic alterations. ALL in infants is a rare subset often associated with MLL rearrangements, B cell precursor lineage lacking CD10 (pro-B ALL) and a prenatal origin in utero. Infant T-cell ALL (T-ALL) is a very rare and poorly defined entity with a worse outcome in general. The availability to us of a unique series of 13 infant T-ALL cases (≤12 months) along with 12 remission cases allowed us to perform a genome-wide study of the clonotypic alterations present in these leukaemias and to elucidate more definitively the critical genomic hits required to drive the emergence of overt disease.
The main clinical and demographic characteristics observed in our series were a median age of 9 months, no predominance of gender and a high WBC count (≥ 50,000) in 12 out of 13 cases at diagnosis. The infants were treated according to Brazilian GBTLI protocol (n=3), BFM protocol (n=2), EORTC (n=3) and INTERFANT (n=5). All samples were analysed at diagnosis for the main T-ALL associated abnormalities and our results showed 4 cases mutated for NOTCH1. One case also presented with an FBXW7 mutation concomitant with wild type NOTCH1. Two cases showed PTEN mutations and all cases were germ line for IL7R. Furthermore, we did not observe any case with SIL-TAL1 or TLX3 rearrangements. TCRG & D were both rearranged in 7 cases while 1 case presented with only TCRG rearrangement and 1 case with only TCRD rearranged. Seven cases also showed rearrangement of TCRB and 1 case showed no receptor gene rearrangement at all. This latter case also had a classical ETP profile. MLL rearrangements were detected by FISH in 4 out of 13 cases. All diagnostic samples were analysed by SNP-array to identify genomic losses and gains. As a summary of the SNP data, a recurrent somatic chromosome 3 deletion was observed in 3 cases. The losses, similar in size, result in the complete deletion of MLF1 and have not previously been described in T-ALL. MLF1 plays a key role in AML and myelodysplastic syndrome leukaemogenesis. Q-PCR and FISH were used to confirm the copy number of MLF1 in those cases analysed. Akin to paediatric T-ALL we observed a PTEN deletion in 1 patient and 2 further cases with an 11p13 deletion that could lead to activation of LMO2. One case harboured a large 11q14.1-11q23.2 deletion that includes the important ‘driver’ gene ATM. The deletion of 11q including ATM has been reported in 30% of patients with CLL and at a low rate in ALL. One patient also harboured a TCRB-MYB translocation known to be associated with a young age of onset of T-ALL and an expression signature of proliferation/mitosis. Five out of 13 cases that were negative for MLL gene rearrangement, did show deletions of CDKN2A. These results were verified by Q-PCR copy number analysis and FISH. Overall, the current data suggest that infant T-ALL presents both different and infrequent genetic abnormalities in general when compared to T-ALL in older children and adults.

Disclosures:
No relevant conflicts of interest to declare.