RUNX1 Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Sig...

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Zeitschriftentitel:	Journal of Clinical Oncology
Personen und Körperschaften:	Mendler, Jason H., Maharry, Kati, Radmacher, Michael D., Mrózek, Krzysztof, Becker, Heiko, Metzeler, Klaus H., Schwind, Sebastian, Whitman, Susan P., Khalife, Jihane, Kohlschmidt, Jessica, Nicolet, Deedra, Powell, Bayard L., Carter, Thomas H., Wetzler, Meir, Moore, Joseph O., Kolitz, Jonathan E., Baer, Maria R., Carroll, Andrew J., Larson, Richard A., Caligiuri, Michael A., Marcucci, Guido, Bloomfield, Clara D.
In:	Journal of Clinical Oncology, 30, 2012, 25, S. 3109-3118
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Society of Clinical Oncology (ASCO)
Schlagwörter:	Cancer Research Oncology

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Zusammenfassung:	<jats:sec><jats:title>Purpose</jats:title><jats:p> To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> Younger (< 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P < .001) and inversely associated with NPM1 (P < .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P < .001 in older), overall survival (P = .003 in younger; P < .001 in older), and event-free survival (P < .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation–associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches. </jats:p></jats:sec>
Umfang:	3109-3118
ISSN:	0732-183X 1527-7755
DOI:	10.1200/jco.2011.40.6652