CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia

• Published in: Cancer 2018-08, Vol.124 (16), p.3329-3338
• Main Authors: Zhang, Yang, Wang, Fang, Chen, Xue, Zhang, Yu, Wang, Mingyu, Liu, Hong, Cao, Panxiang, Ma, Xiaoli, Wang, Tong, Zhang, Jianping, Zhang, Xian, Lu, Peihua, Liu, Hongxing
• Format: Article
• Language: English
• Subjects: Abnormalities; Acute lymphoblastic leukemia; Acute myeloid leukemia; CCAAT/enhancer binding protein α (CEBPA); CCAAT/enhancer-binding protein; colony‐stimulating factor 3 receptor (CSF3R); core‐binding factor β subunit‐myosin heavy‐chain 11 (CBFB‐MYH11); Gene sequencing; Genes; Genetic abnormalities; Leukemia; Leukocytes (neutrophilic); Lymphatic leukemia; Missense mutation; Mutation; Myeloid leukemia; Oncology; Patients; Polymerase chain reaction; Proteins; RNA-directed DNA polymerase; runt‐related transcription factor 1 (RUNX1)‐RUNX1 translocation partner 1 (RUNX1‐RUNX1T1); Runx1 protein; Transcription factors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.31586

Background Mutations in the colony‐stimulating factor 3 receptor (CSF3R) gene occur frequently in chronic neutrophilic leukemia and are rare in de novo acute leukemia. The objective of this study was to assess the incidence of CSF3R mutations in acute leukemia and their association with other genetic abnormalities. Methods Amplicon‐targeted, next‐generation sequencing of 58 genes was performed retrospectively on 1152 patients (acute myeloid leukemia [AML], n = 587; acute lymphoid leukemia [ALL], n = 565). Reverse transcriptase‐polymerase chain reaction analysis was used to detect 35 leukemia‐specific gene fusions. Results CSF3R mutations (26 patients) were detected in 3.6% (13 of 364 patients), 4.6% (8 of 175 patients), and 8.3% (4 of 48 patients) of those with de novo, relapsed, and secondary AML, respectively, and in 0.2% (1 of 565 patients) of those with ALL. In total, 9 distinct CSF3R mutations were detected. Membrane‐proximal missense mutations and cytoplasmic truncations were identified as mutually exclusive. The proportion of patients who had French‐American‐British subtypes M2 and M4 in the CSF3R‐mutated group was significantly greater than that in the CSF3R wild‐type group for both the de novo AML cohort (P = .001) and the relapsed AML cohort (P = .024). All de novo and relapsed AMLs with CSF3R mutations were associated with genetic alterations in transcription factors, including RUNX1‐RUNX1T1, CBFB‐MYH11, double‐mutated CCAAT/enhancer binding protein α (CEBPAdm), and NPM1 mutations; and core‐binding factor gene abnormalities and CEBPAdm accounted for 90.5% (19 of 21 patients). Conclusions CSF3R mutations are uncommon in AML; however, when they occur, they are often associated with core‐binding factor gene abnormalities and CEBPAdm. An in‐depth understanding of the interaction between these genetic alterations could facilitate a clearer understanding of the role of CSF3R mutations in AML development and may be used for disease classification, prognosis, and the development of targeted therapy. Colony‐stimulating factor 3 receptor (CSF3R) is mutated in 3.6% of de novo acute myeloid leukemia (AML), of which 90% is associated with abnormalities in core‐binding factor genes (including RUNX1‐RUNX1T1 and CBFB‐MYH11) and double‐mutated CEBPA. The clonal evolution and mutational pattern of CSF3R mutations in de novo AML are different from those in AML with myelodysplasia‐related changes.