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Clinical Trial
. 2012 Sep 1;30(25):3109-18.
doi: 10.1200/JCO.2011.40.6652. Epub 2012 Jul 2.

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 signatures

Jason H Mendler  1 , Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Heiko Becker, Klaus H Metzeler, Sebastian Schwind, Susan P Whitman, Jihane Khalife, Jessica Kohlschmidt, Deedra Nicolet, Bayard L Powell, Thomas H Carter, Meir Wetzler, Joseph O Moore, Jonathan E Kolitz, Maria R Baer, Andrew J Carroll, Richard A Larson, Michael A Caligiuri, Guido Marcucci, Clara D Bloomfield
Affiliations
Clinical Trial

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 signatures

Jason H Mendler et al. J Clin Oncol. .

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

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Figures

Fig 1.
Fig 1.
(A) Disease-free survival, (B) overall survival, and (C) event-free survival of patients younger than age 60 years with cytogenetically normal acute myeloid leukemia according to RUNX1 mutation status. RUNX1 mut, RUNX1 mutated; RUNX1 wt, RUNX1 wild type.
Fig 2.
Fig 2.
(A) Disease-free survival, (B) overall survival, and (C) event-free survival of patients age 60 years and older with cytogenetically normal acute myeloid leukemia according to RUNX1 mutation status. RUNX1 mut, RUNX1 mutated; RUNX1 wt, RUNX1 wild type.
Fig 3.
Fig 3.
(A) Heat map of the gene expression signature associated with RUNX1 mutations (mut) in older patients with NPM1 wild-type (wt) status. Upregulated and downregulated genes mentioned in the text are indicated. (B) Heat map of the microRNA expression signature associated with RUNX1 mutations in older patients with NPM1 wild-type status.
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