Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia

Antonio R Lucena-Araujo, Juan L Coelho-Silva, Diego A Pereira-Martins, Douglas R Silveira, Luisa C Koury, Raul A M Melo, Rosane Bittencourt, Katia Pagnano, Ricardo Pasquini, Elenaide C Nunes, Evandro M Fagundes, Ana B Gloria, Fábio Kerbauy, Maria de Lourdes Chauffaille, Israel Bendit, Vanderson Rocha, Armand Keating, Martin S Tallman, Raul C Ribeiro, Richard DillonArnold Ganser, Bob Löwenberg, P J M Valk, Francesco Lo-Coco, Miguel A Sanz, Nancy Berliner, Eduardo M Rego

Research output: Contribution to journalArticle

Abstract

By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality (P < .001), remission (P = .004), overall survival (P < .001), cumulative incidence of relapse (P = .028), disease-free survival (P = .03), and event-free survival (P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.

Original languageEnglish
Pages (from-to)951-959
Number of pages9
JournalBlood
Volume134
Issue number12
DOIs
Publication statusPublished - Sep 19 2019

Keywords

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Biomarkers, Pharmacological/analysis
  • Biomarkers, Tumor/analysis
  • Cohort Studies
  • DNA Mutational Analysis/methods
  • Female
  • Gene Expression Profiling/methods
  • Gene Expression Regulation, Leukemic/drug effects
  • Humans
  • Leukemia, Promyelocytic, Acute/diagnosis
  • Male
  • Middle Aged
  • Molecular Diagnostic Techniques/methods
  • Mutation
  • Prognosis
  • Tandem Repeat Sequences/genetics
  • Transcriptome
  • Treatment Outcome
  • Tretinoin/administration & dosage
  • Young Adult
  • fms-Like Tyrosine Kinase 3/genetics

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  • Cite this

    Lucena-Araujo, A. R., Coelho-Silva, J. L., Pereira-Martins, D. A., Silveira, D. R., Koury, L. C., Melo, R. A. M., Bittencourt, R., Pagnano, K., Pasquini, R., Nunes, E. C., Fagundes, E. M., Gloria, A. B., Kerbauy, F., de Lourdes Chauffaille, M., Bendit, I., Rocha, V., Keating, A., Tallman, M. S., Ribeiro, R. C., ... Rego, E. M. (2019). Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia. Blood, 134(12), 951-959. https://doi.org/10.1182/blood.2019000239