An integrative approach reveals genetic complexity and epigenetic perturbation in acute promyelocytic leukemia

a single institution experience

Nina Rahimi, Yanming Zhang, Alain Mina, Jessica K Altman, Madina Sukhanova, Olga Frankfurt, Lawrence J Jennings, Xinyan Lu, Amir Behdad, Qing Ching Chen, Yi-Hua Chen, Juehua Gao*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is defined by the presence of the translocations that mostly involve the RARA gene. The most frequent translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have shown that other cooperative mutations are required for the development of APL after the initiating event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our institution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations are frequent events in APL. In addition to the previously reported recurrent cooperative mutations in the FLT3, WT1, and RAS genes, we identified mutations in several epigenetic modifiers, including TET2, EZH2, and DNMT3A, co-occurring with either FLT3 or WT1 mutations. Mutations of the WT1 gene and chromosome 11p copy neutral loss of heterozygosity affecting WT1 are present in a third of the cases in our series. Two-thirds of APL cases in our study demonstrated a global reduction but focal accumulation of H3K27 methylase (H3K27me) expression, indicating a disorganized chromatin methylation pattern with generally more accessible chromatin status. Our study confirmed genetic complexity of APL and revealed that epigenetic aberrations are more common than previously expected. Although epigenetic modulation is not a common treatment strategy in APL, targeting this pathway may have some clinical utility in refractory or relapsed APL cases.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalHuman pathology
Volume91
DOIs
StatePublished - Sep 1 2019

Fingerprint

Acute Promyelocytic Leukemia
Epigenomics
Mutation
Genes
Chromatin
Loss of Heterozygosity
Acute Myeloid Leukemia
Cytogenetics
Methylation
Single Nucleotide Polymorphism
Chromosomes

Keywords

  • Acute promyelocytic leukemia
  • Copy neutral loss of heterozygosity
  • Epigenetics
  • Next-generation sequencing
  • SNP array
  • Somatic mutations

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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title = "An integrative approach reveals genetic complexity and epigenetic perturbation in acute promyelocytic leukemia: a single institution experience",
abstract = "Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is defined by the presence of the translocations that mostly involve the RARA gene. The most frequent translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have shown that other cooperative mutations are required for the development of APL after the initiating event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our institution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations are frequent events in APL. In addition to the previously reported recurrent cooperative mutations in the FLT3, WT1, and RAS genes, we identified mutations in several epigenetic modifiers, including TET2, EZH2, and DNMT3A, co-occurring with either FLT3 or WT1 mutations. Mutations of the WT1 gene and chromosome 11p copy neutral loss of heterozygosity affecting WT1 are present in a third of the cases in our series. Two-thirds of APL cases in our study demonstrated a global reduction but focal accumulation of H3K27 methylase (H3K27me) expression, indicating a disorganized chromatin methylation pattern with generally more accessible chromatin status. Our study confirmed genetic complexity of APL and revealed that epigenetic aberrations are more common than previously expected. Although epigenetic modulation is not a common treatment strategy in APL, targeting this pathway may have some clinical utility in refractory or relapsed APL cases.",
keywords = "Acute promyelocytic leukemia, Copy neutral loss of heterozygosity, Epigenetics, Next-generation sequencing, SNP array, Somatic mutations",
author = "Nina Rahimi and Yanming Zhang and Alain Mina and Altman, {Jessica K} and Madina Sukhanova and Olga Frankfurt and Jennings, {Lawrence J} and Xinyan Lu and Amir Behdad and Chen, {Qing Ching} and Yi-Hua Chen and Juehua Gao",
year = "2019",
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day = "1",
doi = "10.1016/j.humpath.2019.05.008",
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volume = "91",
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T1 - An integrative approach reveals genetic complexity and epigenetic perturbation in acute promyelocytic leukemia

T2 - a single institution experience

AU - Rahimi, Nina

AU - Zhang, Yanming

AU - Mina, Alain

AU - Altman, Jessica K

AU - Sukhanova, Madina

AU - Frankfurt, Olga

AU - Jennings, Lawrence J

AU - Lu, Xinyan

AU - Behdad, Amir

AU - Chen, Qing Ching

AU - Chen, Yi-Hua

AU - Gao, Juehua

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is defined by the presence of the translocations that mostly involve the RARA gene. The most frequent translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have shown that other cooperative mutations are required for the development of APL after the initiating event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our institution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations are frequent events in APL. In addition to the previously reported recurrent cooperative mutations in the FLT3, WT1, and RAS genes, we identified mutations in several epigenetic modifiers, including TET2, EZH2, and DNMT3A, co-occurring with either FLT3 or WT1 mutations. Mutations of the WT1 gene and chromosome 11p copy neutral loss of heterozygosity affecting WT1 are present in a third of the cases in our series. Two-thirds of APL cases in our study demonstrated a global reduction but focal accumulation of H3K27 methylase (H3K27me) expression, indicating a disorganized chromatin methylation pattern with generally more accessible chromatin status. Our study confirmed genetic complexity of APL and revealed that epigenetic aberrations are more common than previously expected. Although epigenetic modulation is not a common treatment strategy in APL, targeting this pathway may have some clinical utility in refractory or relapsed APL cases.

AB - Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is defined by the presence of the translocations that mostly involve the RARA gene. The most frequent translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have shown that other cooperative mutations are required for the development of APL after the initiating event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our institution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations are frequent events in APL. In addition to the previously reported recurrent cooperative mutations in the FLT3, WT1, and RAS genes, we identified mutations in several epigenetic modifiers, including TET2, EZH2, and DNMT3A, co-occurring with either FLT3 or WT1 mutations. Mutations of the WT1 gene and chromosome 11p copy neutral loss of heterozygosity affecting WT1 are present in a third of the cases in our series. Two-thirds of APL cases in our study demonstrated a global reduction but focal accumulation of H3K27 methylase (H3K27me) expression, indicating a disorganized chromatin methylation pattern with generally more accessible chromatin status. Our study confirmed genetic complexity of APL and revealed that epigenetic aberrations are more common than previously expected. Although epigenetic modulation is not a common treatment strategy in APL, targeting this pathway may have some clinical utility in refractory or relapsed APL cases.

KW - Acute promyelocytic leukemia

KW - Copy neutral loss of heterozygosity

KW - Epigenetics

KW - Next-generation sequencing

KW - SNP array

KW - Somatic mutations

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