Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia

Corine J. Hess, Johannes Berkhof, Fedor Denkers, Gert J. Ossenkoppele, Jan P. Schouten, Joost J. Oudejans, Quinten Waisfisz, Gerrit J. Schuurhuis

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS). Patients and Methods: The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD -/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation. Results: High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(I) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months). Conclusion: High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.

Original languageEnglish
Pages (from-to)1209-1215
Number of pages7
JournalJournal of Clinical Oncology
Volume25
Issue number10
DOIs
Publication statusPublished - 1 Apr 2007

Cite this

@article{ac870ebd0c0b4517beb6f0c943c9640b,
title = "Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia",
abstract = "Purpose: By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS). Patients and Methods: The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD -/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation. Results: High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(I) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months). Conclusion: High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.",
author = "Hess, {Corine J.} and Johannes Berkhof and Fedor Denkers and Ossenkoppele, {Gert J.} and Schouten, {Jan P.} and Oudejans, {Joost J.} and Quinten Waisfisz and Schuurhuis, {Gerrit J.}",
year = "2007",
month = "4",
day = "1",
doi = "10.1200/JCO.2006.08.4061",
language = "English",
volume = "25",
pages = "1209--1215",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
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Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia. / Hess, Corine J.; Berkhof, Johannes; Denkers, Fedor; Ossenkoppele, Gert J.; Schouten, Jan P.; Oudejans, Joost J.; Waisfisz, Quinten; Schuurhuis, Gerrit J.

In: Journal of Clinical Oncology, Vol. 25, No. 10, 01.04.2007, p. 1209-1215.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia

AU - Hess, Corine J.

AU - Berkhof, Johannes

AU - Denkers, Fedor

AU - Ossenkoppele, Gert J.

AU - Schouten, Jan P.

AU - Oudejans, Joost J.

AU - Waisfisz, Quinten

AU - Schuurhuis, Gerrit J.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Purpose: By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS). Patients and Methods: The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD -/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation. Results: High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(I) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months). Conclusion: High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.

AB - Purpose: By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS). Patients and Methods: The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD -/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation. Results: High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(I) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months). Conclusion: High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.

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U2 - 10.1200/JCO.2006.08.4061

DO - 10.1200/JCO.2006.08.4061

M3 - Article

VL - 25

SP - 1209

EP - 1215

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 10

ER -