Frequency, Characteristics and Prognostic Significance of RUNX1 mutations in Patients with Acute Myeloid Leukemia, Not Otherwise Specified
Authors: Bae Mi-Hyun , Cho Young-Uk , Kim Bohyun , Lee Dong Hyun , Jang Seongsoo , Seo Eul-Ju , Park Chan-Jeoung , Kim Dae-Young , Lee Jung-Hee , Lee Je-Hwan , Lee Kyoo-Hyung , Chang Yoon Hwan , Kim In-Suk 
Published: October 2019

Abstract
Background: Somatic mutations in RUNX1 gene have been identified in a substantial proportion of patients with de novo acute myeloid leukemia (AML). It is suggested as a new candidate molecular marker and, therefore, is suggested to be routinely performed at the diagnostic stage of AML. Despite its clinical importance, however, previous cohorts have been heterogeneous in terms of cytogenetic and molecular subtypes of AML. Here, the aim of this study was to evaluate the frequency, biologic characteristics, and prognostic significance of RUNX1 mutations focusing on patients with AML, not otherwise specified (NOS).
Methods: Diagnostic samples from 202 patients with AML were analyzed for RUNX1 mutations. We excluded AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and therapy-related AML because these entities have prognostic relevances of their own. RUNX1 mutations were detected using standard PCR techniques and direct sequencing.
Results: RUNX1 mutations were found in 27 (13.4%) patients. The mutations were clustered in Runt homology domain (13, 48.1%) and transactivation domain (9, 33.3%). Frameshift mutations were most common (52.9%), followed by missense mutations (35.3%) and nonsense mutations (11.8%). As shown in Table 1, patients with RUNX1 mutations had a lower platelet count (P = 0.03), a higher rate of trisomy 8 (P = 0.02) and trisomy 13 (P = 0.039), and a trend toward older age (P = 0.063) than patients without mutations. Presence of RUNX1 mutations and NPM1 or CEBPA mutations were mutually exclusive. At the median follow-up of 12.1 months, RUNX1 mutations predicted for shorter overall survival (OS; P = 0.007) and relapse-free survival (RFS; P = 0.003). In the multivariate analysis, RUNX1 mutation was a significant marker for inferior OS (hazard ratio, 3.037; P = 0.014) and RFS (hazard ratio, 5.699; P = 0.001).
Conclusion: The findings of our study further strengthen the previous data about RUNX1 mutations in AML. Furthermore, AML NOS with RUNX1 mutations is characterized by distinct biology and is associated with adverse clinical outcome. Our study supports the notion that RUNX1 mutational status would be integrated into diagnostic workup of AML, particularly for AML, NOS subgroup.
Table 1. Clinical and biologic features of the cohort by RUNX1 mutations RUNX1 mutations P -value Mutated, n (%) Wild type, n (%) Number 27 (13.4) 175 (86.6) Male sex 17 (63.0) 94 (53.7) 0.489 Median age, years (range) 63 (14 - 80) 55 (1 - 83) 0.063 WBC count, ¡¿109/L (median, range) 7.9 (1.1 - 133.3) 14.0 (0.8 - 231.3) 0.636 Hemoglobin, g/dL (median, range) 8.6 (5.0 - 10.6) 8.8 (4.1 - 17.3) 0.376 Platelet count, ¡¿109/L (median, range) 35 (14 - 230) 59 (9 - 900) 0.03 Blood blasts, % (median, range) 29 (0 - 94) 38.5 (0 - 93) 0.312 FAB subtypes  M0 3 (11.1) 11 (6.3) 0.609  M1, M2 21 (77.8) 129 (73.7) 0.831  M4, M5 3 (11.1) 27 (15.4) 0.767  M6, M7 0 8 (4.6) 0.546 Cytogenetic abnormalities  Normal karyotype (%) 11 (40.7) 104 (59.4) 0.106  Trisomy 8 (%) 5 (18.5) 8 (4.6) 0.02  Trisomy 11 (%) 1 (3.7) 4 (2.3) 0.823  Trisomy 13 (%) 3 (11.1) 3 (1.7) 0.039  Trisomy 21 (%) 1 (3.7) 2 (1.1) 0.866 Distribution of other mutations  FLT3 -ITD 5 (18.5) 50 (28.6) 0.39  FLT3 -TKD 1 (3.7) 4 (2.3) 0.823  NPM1 0 55 (31.4) 0.002  CEBPA 0 17 (9.7) 0.187  MLL -PTD 1 (3.7) 14 (8.0) 0.691

Disclosures
No relevant conflicts of interest to declare.