Frontiers in Oncology (Apr 2019)

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

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

DOI
https://doi.org/10.3389/fonc.2019.00316
Journal volume & issue
Vol. 9

Abstract

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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, n = 27), immature (n = 38), early cortical (n = 15), cortical (n = 50), late cortical (n = 53), CD4/CD8 double negative mature (n = 31), double positive mature (n = 35) and simple positive mature (n = 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 CDKN2A/Bdel (71.4%), NOTCH1mut (47.6%) and FBXW7mut (17%). ETP-ALL had frequent FLT3mut (22.2%) and SUZ12del (16.7%) (p < 0.001), while CDKN2A/Bdel were rarely found in this subtype (p < 0.001). The early cortical T-ALL subtype had high frequencies of NOTCH1mut and IL7Rmut (71%, 28.6%, respectively), whereas, mature T-ALL with double positive CD4/CD8 had the highest frequencies of STIL-TAL1 (36.7%), LEF1del (27.3%) and CASP8AP2del (22.7%). The co-existence of two groups of T-ALL with NOTCH1mut/IL7Rmut, and with TLX3/SUZ12del/NF1del/IL7Rmut, were characterized with statistical significance (p < 0.05) but only STIL-TAL1 (pOS 47.5%) and NOTCH1WT/FBXW7WT (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 NOTCH1/FBXW7 and STIL-TAL1 rearrangement had a prognostic impact, independent of immunophenotype.

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