AUTHOR=Noronha Elda Pereira , Marques Luísa Vieira Codeço , Andrade Francianne Gomes , Thuler Luiz Claudio Santos , Terra-Granado Eugênia , Pombo-de-Oliveira Maria S. ,  Brazilian Collaborative Study Group of Acute Leukemia , da Paz Zampier Carolina , da Conceição Barbosa Thayana , Chagas Neto Paulo , Dallapicola Brisson Gisele , dos Santos Bueno Filipe Vicente , Cezar Sardou Ingrid , Gonçalves Aguiar Bruno , Silva Dias Anna Carolina , de Brito Patrícia Carneiro , Pedral Sampaio Geraldo , Antônio Gomes Oliveira Raimundo , de Oliveira Claudia Teresa , Casagranda César , Ramos Vera Geni , Ribeiro Neves Gustavo , Maria Quezado Magalhães Isis , Carlos Córdoba José , Teixeira Costa Juliana , Ferreira Marques Rebeca , Pereira de Souza Barros Renata , Sarkis Alves Renata , Guedes Renato , Epelman Sidnei 

TITLE=The Profile of Immunophenotype and Genotype Aberrations in Subsets of Pediatric T-Cell Acute Lymphoblastic Leukemia

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00316

DOI=10.3389/fonc.2019.00316

ISSN=2234-943X

ABSTRACT=<p>T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous malignancy, which reflects distinctive stages of T-cell differentiation arrest. We have revisited a cohort of pediatric T-ALL, in order to test if immunophenotypes associated with molecular alterations would predict the patient's outcome. Genetic mutations, translocations and copy number alterations were identified through Sanger sequencing, RT-PCR, FISH and multiplex ligation-dependent probe amplification (MLPA). We defined 8 immunophenotypic T-ALL subtypes through multiparametric flow cytometry: early T-cell precursor (ETP, <italic>n</italic> = 27), immature (<italic>n</italic> = 38), early cortical (<italic>n</italic> = 15), cortical (<italic>n</italic> = 50), late cortical (<italic>n</italic> = 53), CD4/CD8 double negative mature (<italic>n</italic> = 31), double positive mature (<italic>n</italic> = 35) and simple positive mature (<italic>n</italic> = 31) T-ALL. Deletions (del) or amplifications (amp) in at least one gene were observed in 87% of cases. The most frequent gene alterations were <italic>CDKN2A/B</italic><sup>del</sup> (71.4%), <italic>NOTCH1</italic><sup>mut</sup> (47.6%) and <italic>FBXW7</italic><sup>mut</sup> (17%). ETP-ALL had frequent <italic>FLT3</italic><sup>mut</sup> (22.2%) and <italic>SUZ12</italic><sup>del</sup> (16.7%) (<italic>p</italic> &lt; 0.001), while <italic>CDKN2A/B</italic><sup>del</sup> were rarely found in this subtype (<italic>p</italic> &lt; 0.001). The early cortical T-ALL subtype had high frequencies of <italic>NOTCH1</italic><sup>mut</sup> and <italic>IL7R</italic><sup>mut</sup> (71%, 28.6%, respectively), whereas, mature T-ALL with double positive CD4/CD8 had the highest frequencies of <italic>STIL-TAL1</italic> (36.7%), <italic>LEF1</italic><sup>del</sup> (27.3%) and <italic>CASP8AP2</italic><sup>del</sup> (22.7%). The co-existence of two groups of T-ALL with <italic>NOTCH1</italic><sup>mut</sup><italic>/IL7R</italic><sup>mut</sup>, and with <italic>TLX3/SUZ12</italic><sup>del</sup><italic>/NF1</italic><sup>del</sup>/<italic>IL7R</italic><sup>mut</sup>, were characterized with statistical significance (<italic>p</italic> &lt; 0.05) but only <italic>STIL-TAL1</italic> (pOS 47.5%) and <italic>NOTCH1</italic><sup>WT</sup>/<italic>FBXW7</italic><sup>WT</sup> (pOS 55.3%) are predictors of poor T-ALL outcomes. In conclusion, we have observed that 8 T-ALL subgroups are characterized by distinct molecular profiles. The mutations in <italic>NOTCH1/FBXW7</italic> and <italic>STIL-TAL1</italic> rearrangement had a prognostic impact, independent of immunophenotype.</p>