High Frequency of RUNX1 Mutation in Acute Myeloid Leukemia at Puerto Rico
Authors: Marrero William D. , Cintron-Colon Hector R , Cruz Steven , Rodriguez-Arocho Cristian I. , Caceres William , DiNardo Courtney D. , Cruz-Chacon Alexis M. 
Published: December 2023

Acute Myeloid Leukemia (AML) is the most common form of acute leukemia in adults, with a median age at diagnosis of 68 years. Recurrent genomic abnormalities are established as diagnostic, prognostic markers, and play an essential role in leukemogenesis. For instance, loss-of-function mutations of the runt-related transcription factor-1 (RUNX1) have been associated with distinct clinical and genetic features and overall adverse risk in adult AML. Lack of a specific targeted therapy and resistance to standard intensive chemotherapy likely accounts for the poorer outcome observed in AML expressing RUNX1. Additionally, germline RUNX1 mutations result in the well-described autosomal-dominant familial platelet disorder with predisposition to hematologic malignancies. Previuos studies has identified mutant RUNX1 in 5-10% of patients at a median age of 68 years old.
The objective of our retrospective study was to identify the incidence and characteristics of RUNX1 mutations in our population. RUNX1 plays an important role in the regulation and differentiation of normal hematopoietic stem cells. Therefore, intragenic mutation of RUNX1 leads to impaired hematopoiesis and ultimately leukemia.
The study examined newly diagnosed (ND) patients-AML with RUNX1 mutation by NGS; that were at least 18 years of age or older with cytogenetic and molecular analysis in a period of 4 years (2019-2022). According to the Puerto Rico Cancer Registry from 2015 to 2019 a total of 551 cases of AML were reported. All data regarding demographic, bone marrow biopsy, cytogenetics, and molecular markers were obtained from electronic medical record at San Juan City Hospital with institutional review board approval in acordance with the Declaration of Helsinki. The San Juan City Hospital is the major referral center on the island for initial evaluation and management of AML.
A total of 157 patients with ND AML were identified during the study period. 58% female and 42% male with a median age of 57 years old at time of diagnosis. Compared to an expected ~5-10% incidence of RUNX1 mutations, our study population revealed the presence of RUNX1 in 24% of our AML patients, with a median age less than 60 years old.
More specificially within the 37 patients with RUNX1 mutations, 46% female and 54% male with a median age of 56 years old with an average variable allele frequency(VAF) of 40%. Complex cytogenetics was identified in 41% of RUNX1 cases. Co-occuring mutation of RUNX1 with TP53 was identified in 19% of patients.
Our study showed a high expression of RUNX1 in Puerto Rican ND-AML. The median age at diagnosis and the average VAF suggest the possibility of a germline RUNX1 in our population. Previous studies in medical literature have identified a correlation for germline RUNX1 in patients diagnosed before 60 years old and with a VAF above 40%. Future studies with larger sample size and longer follow-up may confirm if there is a germline predisposition in our patients for RUNX1.