Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28...

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Main Authors: Ezhilarasi Chendamarai, Saravanan Ganesan, Ansu Abu Alex, Vandana Kamath, Sukesh C Nair, Arun Jose Nellickal, Nancy Beryl Janet, Vivi Srivastava, Kavitha M Lakshmi, Auro Viswabandya, Aby Abraham, Mohammed Aiyaz, Nandita Mullapudi, Raja Mugasimangalam, Rose Ann Padua, Christine Chomienne, Mammen Chandy, Alok Srivastava, Biju George, Poonkuzhali Balasubramanian, Vikram Mathews
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2015-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4378855?pdf=render
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spelling doaj-df7684acf6474b0e8b346f8d42ae963e2020-11-25T01:30:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e012191210.1371/journal.pone.0121912Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.Ezhilarasi ChendamaraiSaravanan GanesanAnsu Abu AlexVandana KamathSukesh C NairArun Jose NellickalNancy Beryl JanetVivi SrivastavaKavitha M LakshmiAuro ViswabandyaAby AbrahamMohammed AiyazNandita MullapudiRaja MugasimangalamRose Ann PaduaChristine ChomienneMammen ChandyAlok SrivastavaBiju GeorgePoonkuzhali BalasubramanianVikram MathewsThere is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.http://europepmc.org/articles/PMC4378855?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Ezhilarasi Chendamarai
Saravanan Ganesan
Ansu Abu Alex
Vandana Kamath
Sukesh C Nair
Arun Jose Nellickal
Nancy Beryl Janet
Vivi Srivastava
Kavitha M Lakshmi
Auro Viswabandya
Aby Abraham
Mohammed Aiyaz
Nandita Mullapudi
Raja Mugasimangalam
Rose Ann Padua
Christine Chomienne
Mammen Chandy
Alok Srivastava
Biju George
Poonkuzhali Balasubramanian
Vikram Mathews
spellingShingle Ezhilarasi Chendamarai
Saravanan Ganesan
Ansu Abu Alex
Vandana Kamath
Sukesh C Nair
Arun Jose Nellickal
Nancy Beryl Janet
Vivi Srivastava
Kavitha M Lakshmi
Auro Viswabandya
Aby Abraham
Mohammed Aiyaz
Nandita Mullapudi
Raja Mugasimangalam
Rose Ann Padua
Christine Chomienne
Mammen Chandy
Alok Srivastava
Biju George
Poonkuzhali Balasubramanian
Vikram Mathews
Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
PLoS ONE
author_facet Ezhilarasi Chendamarai
Saravanan Ganesan
Ansu Abu Alex
Vandana Kamath
Sukesh C Nair
Arun Jose Nellickal
Nancy Beryl Janet
Vivi Srivastava
Kavitha M Lakshmi
Auro Viswabandya
Aby Abraham
Mohammed Aiyaz
Nandita Mullapudi
Raja Mugasimangalam
Rose Ann Padua
Christine Chomienne
Mammen Chandy
Alok Srivastava
Biju George
Poonkuzhali Balasubramanian
Vikram Mathews
author_sort Ezhilarasi Chendamarai
title Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
title_short Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
title_full Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
title_fullStr Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
title_full_unstemmed Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
title_sort comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2015-01-01
description There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.
url http://europepmc.org/articles/PMC4378855?pdf=render
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