Abstract
(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1% of younger patients and 15.9% of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.
Highlights
The genetic diversity of acute myeloid leukemia (AML) and the complexity of its multi-step pathogenesis allow the classification of AML based on molecular events
This study examined the frequency of RUNX1):c.497G>A p.R166Q [46.4] NM_001754.4 ( (RUNX1) mutations in newly diagnosed patients with AML, and their effect on clinical outcomes and treatment response rates, including younger patients receiving chemotherapy and elderly patients receiving hypomethylating agent (HMA)
While RUNX1 mutations are frequently associated with inferior responses to AML therapy, our analysis suggests that the poor outcomes seen in RUNX1 mutations occur primarily within younger patients treated with intensive therapeutic strategies, as well as the subgroup of RUNX1 mutant AML with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/myeloproliferative neoplasms (MPNs))
Summary
The genetic diversity of acute myeloid leukemia (AML) and the complexity of its multi-step pathogenesis allow the classification of AML based on molecular events. The evolution of AML has traditionally been proposed to follow the “two-hit model” [1], in which two classes of mutations are required for cancer development. Class I mutations are activating mutations that stimulate cell survival and proliferation, while class II mutations are inactivating mutations that interfere with hematopoietic differentiation [2]. Runt-related transcription factor 1 (RUNX1) is a key hematopoietic transcription factor that regulates genes involved in myeloid differentiation, and is generally considered to be a classical tumor suppressor (class II) mutation [2]. Mutations of RUNX1 are reported in approximately 10–16% of AML patients [3,4] and 12–24% of myelodysplastic syndrome (MDS) patients [5,6]. Clinical features associated with this mutation include older age, male sex, and absence of cytogenetic abnormalities [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
