Acute Myeloid Leukemia (AML) with Mutated RUNX1
Iris Martin, M.D.
Daynna J. Wolff, Ph.D.
Acute Myeloid Leukemia
Cancer Sub-Classification / Subtype
Acute Myeloid Leukemia (AML) with mutated RUNX1
Definition / Description of Disease
Mutations in RUNX1 are recurrent in de novo acute myeloid leukemia (AML). The runt-related transcription factor 1 (RUNX1) gene at chromosomal band 21q22 is instrumental in regulating hematopoiesis, and when disrupted, leads to a preleukemic state. RUNX1 interacts with core binding factor beta to form the core factor binding complex. The RUNX1 protein activates genes that control hematopoiesis, particularly in the development of hematopoietic stem cells (see https://ghr.nlm.nih.gov/gene/RUNX1). The RUNX1 protein has two functional domains an N-terminal RUNT domain, which mediates DNA-binding as well as an interaction with core-binding-factor beta (CBFB), and a C-terminal transactivation domain.
Synonyms / Terminology
Epidemiology / Prevalence
AML with mutated RUNX1 has been reported in approximately 3% of pediatric and 15% of adult de novo AML patients. RUNX1 mutations are associated with older age and one study suggested an association with male gender.
Patients with AML with mutated RUNX1 have been reported to have a higher bone marrow blast count, although peripheral blood blasts are decreased. Hemoglobin, white blood cell count, and lactate dehydrogenase are all lower in these patients in comparison to those with wildtype RUNX1. AML patients with RUNX1 mutation reportedly demonstrate reduced complete remission rate, poorer relapse-free survival, and poorer overall survival. The NCCN guidelines (v.1.2018) state that RUNX1 mutations have been associated with poor prognosis in AML, whereas 2017 European LeukemiaNet (ELN) recommendations for AML have placed AML patients with mutated RUNX1 in the absence of favorable risk markers in the adverse risk category. There are no therapies directly targeting inactivating alterations in RUNX1. Preclinical studies suggest that RUNX1 mutation may lead to the epigenetic repression of genes involved in apoptosis; treatment with DNA methyltransferase (DNMT) inhibitors may relieve this inhibition. Co-occurrence of RUNX1 and ASXL1 mutation in AML patients has been linked to poor prognosis, including decreased response to induction therapy, increased risk of death, and decreased event-free and overall survival. The presence of RUNX1 mutation in combination with either PHF6 or SRSF2 mutation has been associated with poor prognosis, as compared with patients not harboring a co-mutation, in one study of 2439 newly diagnosed adult AML patients.
Sites of Involvement
The circulating blood and bone marrow are involved in cases of leukemia.
There are not unique morphologic characteristics for this type of AML. Common features such as large blasts with basophilic cytoplasm, large nuclei with fine chromatin, and cytoplasmic azurophilic granules been reported. Several studies have indicated that the cells are typically immature (M0, M1 and M2) and exhibit undifferentiated morphology. Biallelic RUNX1 mutations have been reported in AML-M0 patients who have a complete lack of RUNX1 function in their leukemic cells.
Myeloblasts express CD13, CD34, and HLA-DR. There is variable expression of MPO, CD33, and monocytic markers.
Chromosomal Rearrangements (Gene Fusions)
The RUNX1 gene is involved in the 8;21 translocation (see Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 page), but the AML with mutated RUNX1 subcategory is specific for those cases with a somatic, acquired mutation in the RUNX1 gene.
Characteristic Chromosomal Aberrations / Patterns
Mutated RUNX1 is more common in AML with a normal karyotype, but has also been associated with trisomies as sole abnormalities including +8, +13 (which is a rare entity) and even more rarely +11 and +14. AML with mutated RUNX1 has also been associated with loss of 7q.
Gene Mutations (SNV/INDEL)
RUNX1 mutations involve exons 3-5, the runt homology domain (RHD), and exons 6-8, the transactivation domain. These include intragenic altertions such as frameshift or missense mutations.
|Gene||Mutation||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
RUNX1 mutations are frequently observed together with FLT3-ITD, FLT3-TKD, and MLL-PTD and with mutations in SRSF2 (25%), ASXL1, IDH1, IDH2 and EZH2. RUNX1 and NPM1 mutations have been reported to be mutually exclusive.
|Mutually Exclusive||RUNX1 and NPM1|
Genes and Main Pathways Involved
The RUNX1 gene spans ∼261 kb on 21q and is a transcription factor which both activates and represses transcription, and is involved in developmental gene-expression programs and hematopoiesis. RUNX1 is a frequent site of translocation and mutation in myeloid cancers and the Runx1 protein functions as a tumor suppressor in this context.
The Runx1 protein has several functional domains (RDH, TAD and VWRPY) that interact with multiple proteins resulting in the control of expression of its target genes involved in hematopoietic differentiation, ribosome biogenesis, cell cycle regulation, and p53 and transforming growth factor β signaling pathways. Various mutations have been reported resulting in loss of protein function including missense, nonsense, and framehshift changes which are distributed throughout the protein, particularly within the RHD domain.
Diagnostic Testing Methods
Typically myeloid gene panel testing by massively parallel sequencing (Next Generation Sequencing) or targeted PCR assays that include the exons spanning the functional domains are used to detect RUNX1 mutations.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
AML patients with RUNX1 mutation reportedly demonstrate reduced complete remission rate, poorer relapse-free survival, and poorer overall survival. The NCCN guidelines (v.1.2018) state that RUNX1 mutations have been associated with poor prognosis in AML, whereas 2017 European LeukemiaNet (ELN) recommendations for AML have placed AML patients with mutated RUNX1 in the absence of favorable risk markers in the adverse risk category. There are no therapies directly targeting inactivating alterations in RUNX1. Preclinical studies suggest that RUNX1 mutation may lead to the epigenetic repression of genes involved in apoptosis; treatment with DNA methyltransferase (DNMT) inhibitors may relieve this inhibition. Co-occurrence of RUNX1 and ASXL1 mutation in AML patients has been linked to poor prognosis, including decreased response to induction therapy, increased risk of death, and decreased event-free and overall survival. The presence of RUNX1 mutation in combination with either PHF6 or SRSF2 mutation has been associated with poor prognosis, as compared with patients not harboring a co-mutation, in one study of 2439 newly diagnosed adult AML patients.
Familial platelet disorder with predisposition to acute myeloid leukemia (FPDMM) is a rare autosomal dominant disorder with thrombocytopenia, platelet dysfunction, bleeding propensity, and a significant risk of hematological malignancies, especially myelodysplastic syndromes and AML. Patients with this disorder have germline mutations in RUNX1.
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