HAEM4Backup:Acute Myeloid Leukemia (AML) with Mutated RUNX1

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Primary Author(s)*

Iris Martin, M.D.

Daynna J. Wolff, Ph.D.

Cancer Category/Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

Acute Myeloid Leukemia (AML) with mutated RUNX1[1]

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

None

Epidemiology / Prevalence

AML with mutated RUNX1 has been reported in approximately 3% of pediatric and 15% of adult de novo AML patients[2][3][4][5]. RUNX1 mutations are associated with older age[1] and one study suggested an association with male gender[2].

Clinical Features

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[1]. AML patients with RUNX1 mutation reportedly demonstrate reduced complete remission rate, poorer relapse-free survival, and poorer overall survival[2][6][7][8][9]. 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[10][11] 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[12]. 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[8][13][14]. 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[8].

Sites of Involvement

The circulating blood and bone marrow are involved in cases of leukemia.

Morphologic Features

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[1]. Several studies have indicated that the cells are typically immature (M0, M1 and M2) and exhibit undifferentiated morphology[15]. Biallelic RUNX1 mutations have been reported in AML-M0 patients who have a complete lack of RUNX1 function in their leukemic cells[16][17].

Immunophenotype

Myeloblasts express CD13, CD34, and HLA-DR. There is variable expression of MPO, CD33, and monocytic markers.

Finding Marker
Positive (universal) CD13
Positive (subset) MPO
Positive (subset) CD33

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[15]. AML with mutated RUNX1 has also been associated with loss of 7q[10].

Genomic Gain/Loss/LOH

Not applicable.

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)

Other Mutations

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[1][3][3][8][10][18]. RUNX1 and NPM1 mutations have been reported to be mutually exclusive[3][4][8][18].

Type Gene/Region/Other
Concomitant Mutations
Secondary Mutations
Mutually Exclusive RUNX1 and NPM1

Epigenomics (Methylation)

Not applicable.

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[19][20].

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[18]. 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[18].

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[2][6][7][8][9]. 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[10][11] 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[12]. 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[8][13][14]. 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[8].

Familial Forms

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[18].

Other Information

Not applicable.

Links

RUNX1

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p144-145.
  2. ↑ 2.0 2.1 2.2 2.3 Tang, Jih-Luh; et al. (2009). "AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations". Blood. 114 (26): 5352–5361. doi:10.1182/blood-2009-05-223784. ISSN 1528-0020. PMID 19808697.
  3. ↑ 3.0 3.1 3.2 3.3 Greif, Philipp A.; et al. (2012). "RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes". Haematologica. 97 (12): 1909–1915. doi:10.3324/haematol.2012.064667. ISSN 1592-8721. PMC 3590097. PMID 22689681.
  4. ↑ 4.0 4.1 Mendler, Jason H.; et al. (2012). "RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (25): 3109–3118. doi:10.1200/JCO.2011.40.6652. ISSN 1527-7755. PMC 3732007. PMID 22753902.
  5. ↑ Schuback, Heather L.; et al. (2013). "Somatic characterization of pediatric acute myeloid leukemia using next-generation sequencing". Seminars in Hematology. 50 (4): 325–332. doi:10.1053/j.seminhematol.2013.09.003. ISSN 1532-8686. PMID 24246700.
  6. ↑ 6.0 6.1 Gaidzik, Verena I.; et al. (2011). "RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 29 (10): 1364–1372. doi:10.1200/JCO.2010.30.7926. ISSN 1527-7755. PMID 21343560.
  7. ↑ 7.0 7.1 Schnittger, Susanne; et al. (2011). "RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis". Blood. 117 (8): 2348–2357. doi:10.1182/blood-2009-11-255976. ISSN 1528-0020. PMID 21148331.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Gaidzik, V. I.; et al. (2016). "RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features". Leukemia. 30 (11): 2282. doi:10.1038/leu.2016.207. ISSN 1476-5551. PMID 27804971.
  9. ↑ 9.0 9.1 Metzeler, Klaus H.; et al. (2016). "Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia". Blood. 128 (5): 686–698. doi:10.1182/blood-2016-01-693879. ISSN 1528-0020. PMID 27288520.
  10. ↑ 10.0 10.1 10.2 10.3 Bullinger, Lars; et al. (2017). "Genomics of Acute Myeloid Leukemia Diagnosis and Pathways". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 35 (9): 934–946. doi:10.1200/JCO.2016.71.2208. ISSN 1527-7755. PMID 28297624.
  11. ↑ 11.0 11.1 Döhner, Hartmut; et al. (2017). "Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel". Blood. 129 (4): 424–447. doi:10.1182/blood-2016-08-733196. ISSN 1528-0020. PMC 5291965. PMID 27895058.
  12. ↑ 12.0 12.1 Saunthararajah, Yogen; et al. (2012). "p53-Independent, normal stem cell sparing epigenetic differentiation therapy for myeloid and other malignancies". Seminars in Oncology. 39 (1): 97–108. doi:10.1053/j.seminoncol.2011.11.011. ISSN 1532-8708. PMC 3655437. PMID 22289496.
  13. ↑ 13.0 13.1 Paschka, Peter; et al. (2015). "ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group". Haematologica. 100 (3): 324–330. doi:10.3324/haematol.2014.114157. ISSN 1592-8721. PMC 4349270. PMID 25596267.
  14. ↑ 14.0 14.1 Krauth, M.-T.; et al. (2014). "High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome". Leukemia. 28 (7): 1449–1458. doi:10.1038/leu.2014.4. ISSN 1476-5551. PMID 24402164.
  15. ↑ 15.0 15.1 Haferlach, T.; et al. (2016). "The new provisional WHO entity 'RUNX1 mutated AML' shows specific genetics but no prognostic influence of dysplasia". Leukemia. 30 (10): 2109–2112. doi:10.1038/leu.2016.150. ISSN 1476-5551. PMC 5056958. PMID 27211269.
  16. ↑ Preudhomme, C.; et al. (2000). "High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21". Blood. 96 (8): 2862–2869. ISSN 0006-4971. PMID 11023523.
  17. ↑ Roumier, Christophe; et al. (2003). "M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH)". Blood. 101 (4): 1277–1283. doi:10.1182/blood-2002-05-1474. ISSN 0006-4971. PMID 12393381.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 Sood, Raman; et al. (2017). "Role of RUNX1 in hematological malignancies". Blood. 129 (15): 2070–2082. doi:10.1182/blood-2016-10-687830. ISSN 1528-0020. PMC 5391618. PMID 28179279.
  19. ↑ Silva, Fernando P. G.; et al. (2003). "Identification of RUNX1/AML1 as a classical tumor suppressor gene". Oncogene. 22 (4): 538–547. doi:10.1038/sj.onc.1206141. ISSN 0950-9232. PMID 12555067.
  20. ↑ Rio-Machín, Ana; et al. (2012). "Abrogation of RUNX1 gene expression in de novo myelodysplastic syndrome with t(4;21)(q21;q22)". Haematologica. 97 (4): 534–537. doi:10.3324/haematol.2011.050567. ISSN 1592-8721. PMC 3347656. PMID 22102704.

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