Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent

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Abstract

Background: Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management. Case Presentation: Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time. Conclusions: This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

Original languageEnglish (US)
Article number31
JournalJournal of Hematology and Oncology
Volume9
Issue number1
DOIs
StatePublished - 2016

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Germ Cell and Embryonal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Genetic Testing
Acute Myeloid Leukemia
Mutation
Recurrence
High-Throughput Nucleotide Sequencing
Hematologic Neoplasms
Therapeutics
Disease Management
Rare Diseases
Leukemia
Clone Cells
trametinib
Neoplasms

Keywords

  • Acute myeloid leukemia
  • Germ cell neoplasm
  • High-throughput nucleotide sequencing
  • NRAS
  • Trametinib

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

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title = "Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent",
abstract = "Background: Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management. Case Presentation: Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time. Conclusions: This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.",
keywords = "Acute myeloid leukemia, Germ cell neoplasm, High-throughput nucleotide sequencing, NRAS, Trametinib",
author = "Leonard, {Jessica T.} and Phil Raess and Jennifer Dunlap and Brandon Hayes-Lattin and Jeffrey Tyner and Elie Traer",
year = "2016",
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language = "English (US)",
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journal = "Journal of Hematology and Oncology",
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TY - JOUR

T1 - Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent

AU - Leonard, Jessica T.

AU - Raess, Phil

AU - Dunlap, Jennifer

AU - Hayes-Lattin, Brandon

AU - Tyner, Jeffrey

AU - Traer, Elie

PY - 2016

Y1 - 2016

N2 - Background: Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management. Case Presentation: Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time. Conclusions: This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

AB - Background: Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management. Case Presentation: Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time. Conclusions: This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

KW - Acute myeloid leukemia

KW - Germ cell neoplasm

KW - High-throughput nucleotide sequencing

KW - NRAS

KW - Trametinib

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