Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia.

Jan-Niklas Eckardt ,Michael Kramer ,Gerhard Ehninger ,Alwin Krämer ,Christoph Schliemann ,Ralph Naumann ,Andreas Neubauer ,Volker Kunzmann ,Andreas Hochhaus ,Andreas Burchert ,Johannes Schetelig ,Ulrich Kaiser ,Kerstin Schäfer‐Eckart ,Regina Herbst ,Uwe Platzbecker ,Sebastian Scholl ,Martina Crysandt ,Richard Noppeney ,Christian Thiede ,Markus Schaich ,Claudia D Baldus ,Frank Kroschinsky ,Christoph Röllig ,Jiřı́ Mayer ,Carsten Müller‐Tidow ,Zdeněk Ráčil ,Wolfgang E Berdel ,Hermann Einsele ,Tim H Brümmendorf ,Friedrich Stölzel ,Mathias Hänel ,Sebastian Stasik ,Norbert Frickhofen ,Hubert Serve ,Martin Kaufmann ,Stefan W Krause ,Martin Bornhäuser ,Björn Steffen ,Jan Moritz Middeke

doi:10.3390/cancers13092095

Abstract

Simple SummaryAcute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.

Highlights

Acute myeloid leukemia (AML) is a genetically heterogeneous disease [1]
Univariate a1ann.0da45lEy–L2sN.i2s2130o1)f,7pLr=iOs0kF.,0t2hm8i)sB; whCoaOws neRvoLetrs1,tiasnthiasotmiwcaulelltydivsasigriingainbfilicefiaancnta.anlytsliys adjusting reduced event-free survival (EFS) (LOF mBCORL1: 3.5 months (95%-CI: 1.1–10.1) vs. UF mBCORL1: 6.2 months (95%-CI: 1.9–not reached) vs. wtBCORL1: 7.5 months (95%-CI: 6.7–8.3), HR = 1.521 (95%-CI: 1.045–2.213), p = 0.028); in a multivariable analysis adjusting for a1g1eo,fA16ML type, and ELN2017 risk, this was not statistically significant
Since few patients with mBCOR and mBCORL1 were in the ELN2017 favorable (n = 9 and n = 6, respectively) or ELN2017 adverse-risk groups (n = 12 and n = 6, respectively), we focused on the ELN2017 intermediate-risk group (n = 44 and n = 35, respectively)

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically heterogeneous disease [1]. In the last decade, next-generation sequencing (NGS) has been introduced in hematological practice, and with the use of myeloid gene panels, rare and recurrent mutations have been unveiled, with a majority of patients harboring more than one mutation even within defined AML entities [2]. BCOR was originally described as a repressor of BCL6 [5], and interacts with PCGF1, KDM2B, MLLT3, and IRF8, while BCORL1 interacts with PCGF1, KDM2B, CTBP1, and HDAC [7]. Both BCOR and BCORL1 are core proteins of the polycomb repressive complex PRC1.1. PRC1.1 plays a role in epigenetic modification by adding an ubiquitin to histone H2A at lysine 119 [9]. This process (among others) leads to a silencing of Hox gene clusters [10], and mediates transcriptional

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