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 Dillon; Arnold Ganser; Bob Löwenberg; P J M Valk; Francesco Lo-Coco; Miguel A Sanz; Nancy Berliner; Eduardo M Rego

doi:10.1182/blood.2019000239

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

Fondazione Santa Lucia

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	951-959
Number of pages	9
Journal	Blood
Volume	134
Issue number	12
DOIs	https://doi.org/10.1182/blood.2019000239
Publication status	Published - Sept 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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10.1182/blood.2019000239

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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

Lucena-Araujo, AR, Coelho-Silva, JL, Pereira-Martins, DA, Silveira, DR, Koury, LC, Melo, RAM, Bittencourt, R, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, AB, Kerbauy, F, de Lourdes Chauffaille, M, Bendit, I, Rocha, V, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, B, Valk, PJM, Lo-Coco, F, Sanz, MA, Berliner, N & Rego, EM 2019, 'Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia', Blood, vol. 134, no. 12, pp. 951-959. https://doi.org/10.1182/blood.2019000239

@article{b09b76b76b594d7c8eb680290f7903b8,

title = "Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia",

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.",

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",

author = "Lucena-Araujo, {Antonio R} and Coelho-Silva, {Juan L} and Pereira-Martins, {Diego A} and Silveira, {Douglas R} and Koury, {Luisa C} and Melo, {Raul A M} and Rosane Bittencourt and Katia Pagnano and Ricardo Pasquini and Nunes, {Elenaide C} and Fagundes, {Evandro M} and Gloria, {Ana B} and F{\'a}bio Kerbauy and {de Lourdes Chauffaille}, Maria and Israel Bendit and Vanderson Rocha and Armand Keating and Tallman, {Martin S} and Ribeiro, {Raul C} and Richard Dillon and Arnold Ganser and Bob L{\"o}wenberg and Valk, {P J M} and Francesco Lo-Coco and Sanz, {Miguel A} and Nancy Berliner and Rego, {Eduardo M}",

note = "{\textcopyright} 2019 by The American Society of Hematology.",

year = "2019",

month = sep,

day = "19",

doi = "10.1182/blood.2019000239",

language = "English",

volume = "134",

pages = "951--959",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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TY - JOUR

T1 - Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia

AU - Lucena-Araujo, Antonio R

AU - Coelho-Silva, Juan L

AU - Pereira-Martins, Diego A

AU - Silveira, Douglas R

AU - Koury, Luisa C

AU - Melo, Raul A M

AU - Bittencourt, Rosane

AU - Pagnano, Katia

AU - Pasquini, Ricardo

AU - Nunes, Elenaide C

AU - Fagundes, Evandro M

AU - Gloria, Ana B

AU - Kerbauy, Fábio

AU - de Lourdes Chauffaille, Maria

AU - Bendit, Israel

AU - Rocha, Vanderson

AU - Keating, Armand

AU - Tallman, Martin S

AU - Ribeiro, Raul C

AU - Dillon, Richard

AU - Ganser, Arnold

AU - Löwenberg, Bob

AU - Valk, P J M

AU - Lo-Coco, Francesco

AU - Sanz, Miguel A

AU - Berliner, Nancy

AU - Rego, Eduardo M

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Biomarkers, Pharmacological/analysis

KW - Biomarkers, Tumor/analysis

KW - Cohort Studies

KW - DNA Mutational Analysis/methods

KW - Female

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation, Leukemic/drug effects

KW - Humans

KW - Leukemia, Promyelocytic, Acute/diagnosis

KW - Male

KW - Middle Aged

KW - Molecular Diagnostic Techniques/methods

KW - Mutation

KW - Prognosis

KW - Tandem Repeat Sequences/genetics

KW - Transcriptome

KW - Treatment Outcome

KW - Tretinoin/administration & dosage

KW - Young Adult

KW - fms-Like Tyrosine Kinase 3/genetics

U2 - 10.1182/blood.2019000239

DO - 10.1182/blood.2019000239

M3 - Article

C2 - 31292112

SN - 0006-4971

VL - 134

SP - 951

EP - 959

JO - Blood

JF - Blood

IS - 12

ER -

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

Abstract

Keywords

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