Germline RUNX1 Mutations in RUNX1-Mutated AML More Frequent Than Previously Thought

A small study in Canada shows that the frequency of germline RUNX1 mutations in patients with RUNX1-mutated acute myeloid leukemia (AML) is higher than expected, according to findings published in Blood. These results illustrate the need for increased screening of donor RUNX1 mutation status in patients who are scheduled to undergo a hematopoietic cell transplantation (HCT) from a related donor.

Growing genetic evidence suggests that familial cases of adult myelodysplastic syndromes (MDS)/AML are likely to be more common than previously thought, lead study author Laura Simon, PhD, from the Institute for Research in Immunology and Cancer at the University of Montreal, told ASH Clinical News. “Due to significant heterogeneity in age of presentation and clinical course, RUNX1-familial platelet disorder is frequently undetected until patients present with malignant transformation.” Somatic RUNX1 mutations also can be acquired during leukemic transformation, she noted, “and the lack of proper germline tissue for genetic testing often leads to underdiagnosis of a leukemia predisposition syndrome.”

In this study, Dr. Simon and investigators collected samples from patients with primary AML between 2001 and 2015. A total of 430 patients underwent RNA sequencing, and 44 patients were confirmed to have RUNX1-mutated disease. Another 12 patients had non-RUNX1 mutations.

Next, the researchers performed a differential gene expression analysis and screening of mutations in 80 AML-related genes, which was used to compare and determine the proportion of patients with germline versus somatic RUNX1 mutations. Approximately 30% of the RUNX1 mutations in the AML cohort were germline, comprising missense (n=5), nonsense (n=4), and frameshift (n=3) mutations.

Patients with germline RUNX1 mutations developed leukemia at a younger age than those with somatic RUNX1 mutations (56.5 years vs. 63.5 years, respectively). Four of 12 patients with germline RUNX1 mutations developed leukemia before turning 50 years old (33.3%), while just 2 patients in the somatic RUNX1 mutation group developed leukemia before age 50 (7.1%).

In addition, patients with RUNX1 germline-mutated AML had a higher frequency of NRAS mutations, as well as a higher frequency of other mutations associated with the activation of signaling pathways – notably in the RAS pathway.

“Identifying individuals affected by a leukemia predisposition syndrome is important because they require a unique approach in clinical management,” noted Dr. Simon.

“Patients with AML with RUNX1 mutations display poor overall survival and are candidates to receive HCT.” In individuals who are eligible for allogeneic HCT with a related donor,” she added, genetic analysis may be important to avoid transplant from an asymptomatic RUNX1 mutation carrier.

If a germline RUNX1 mutation and potential underlying predisposition syndrome is identified, said Dr. Simon, it is important to refer the patient for genetic counseling. “Genetic counseling includes obtaining and analyzing a multigenerational medical family history and may impact the [patient with leukemia’s] own treatment, as well as help identify family members at risk and plan for future screening or preventive strategies,” she said.

This study includes several important limitations and raises several questions that should be addressed in future research, Dr. Simon told ASH Clinical News. The analysis, which focused on a small cohort of patients with AML in a single Canadian region, may be limited in terms of generalizability. In addition, larger patient cohorts are needed to further validate the tendency for acquiring NRAS mutations in this patient population.

“To better understand the mechanism leading to AML, we are using whole-genome and whole-exome sequencing to gain insights into tumor heterogeneity and evolution,” added Dr. Simon. “However, such analyses performed in the cohort rely on single patient samples collected at the time of AML diagnosis, which represents an important additional limitation in our study.”

She also noted that the integration of all aspects of leukemia susceptibility into clinical care can be a challenging task. “Our study reinforces the importance of genetic testing and retrieval of a robust family history of first- and second-degree relatives in suspected familial predisposition syndromes, especially in younger patients,” Dr. Simon said. “Identification and characterization of RUNX1 pedigrees is paramount for building the natural history of the disease and establishing data collections that inform on the prognosis and patient outcome.”

The authors report no relevant conflicts of interest.


Simon L, Spinella JF, Yao CY, et al. High frequency of germline RUNX1 mutations in RUNX1 mutated AML patients. Blood. 2020 February 13. [Epub ahead of print]

Inherited hematologic predispositions to AML are increasingly recognized, and this is highlighted in the recent manuscript by Dr. Simon and colleagues, which evaluated a cohort of patients with AML and RUNX1 mutations.

In an adult population of AML, the researchers found that, of 44 patients with RUNX1 mutations with large variant allele frequency size (>30%), the RUNX1 mutation was of germline inheritance in 12 patients (~30%). This incidence is significantly more frequent than previously estimated and is particularly relevant to AML clinicians, as RUNX1 mutations occur in approximately 10% of patients with MDS and AML.

The identification of germline mutations is critically important for patients, especially those undergoing allogenic HCT, where family member donors should be screened to confirm the absence of the familial mutation prior to transplant to prevent issues of graft failure and donor-derived leukemia, which are increasingly recognized and likely to be more common when donors have germline mutations predisposing them to MDS/AML.

While larger datasets will be needed to confirm this estimate, as well as the pathogenicity of several of these germline variants (only 4 of the germline variants had been previously reported), the conclusion that hereditary hematologic malignancies are more frequent than previously estimated is readily apparent.

Courtney DiNardo, MD
The University of Texas MD Anderson Cancer Center
Houston, TX