RUNX1-Familial Platelet Disorder (PDQ®): Genetics - Health Professional Information [NCI]

Introduction and Clinical Manifestations of RUNX1–Familial Platelet Disorder (RUNX1-FPD)

A concerted effort is being made within the genetics community to use the term, variant rather than the term, mutation to describe genetic differences in the germline. These variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term, pathogenic variant to describe a disease-causing mutation. In this summary, the term, somatic mutations will be used to describe acquired genetic changes that arise in the hematopoietic system (blood stem cells and blood progenitor cells). For more information about variant classification, see the Cancer Genetics Overview summary.

RUNX1 (Runt-related transcription factor 1) is a key transcription factor involved in hematopoietic differentiation, and it is one of the most commonly mutated genes in myeloid malignancies.[1]

Inherited pathogenic variants in the RUNX1 gene lead to an autosomal dominant hereditary cancer syndrome called RUNX1-familial platelet disorder (RUNX1-FPD) (also referred to as FPD with a propensity towards myeloid malignancies [FPD/MM] or acute myeloid leukemia [FPD/AML]).[2] Familial platelet functional defects have been clinically recognized for several decades.[3] In 1999, RUNX1 was the first gene found to be associated with FPD/MM. RUNX1-FPD was the first germline predisposition syndrome associated with myeloid malignancies. In 2016, the World Health Organization (WHO) incorporated germline RUNX1 pathogenic variants under a newly created subcategory of myeloid neoplasms called, "myeloid neoplasms with germline predisposition and preexisting platelet disorders."[4] The WHO's inclusion of RUNX1-FPD in its classification guidelines has increased public awareness of this disorder.

Germline RUNX1 pathogenic variants leading to RUNX1-FPD are associated with the following:[5]

• Lifetime mild to moderate thrombocytopenia associated with aspirin-like functional platelet defects.
• Approximately a 44% lifetime risk of developing myelodysplastic syndrome (MDS), AML, or T-cell acute lymphoblastic leukemia (T-ALL).

Although these are the most commonly reported hematologic cancers seen in individuals with RUNX1-FPD, other cancers have also been reported, including B-cell malignancies and myeloproliferative neoplasms.[6,7,8,9] There is a high penetrance of thrombocytopenia and underlying platelet dysfunction in individuals with RUNX1-FPD. Thrombocytopenia is often recognized during childhood, although it has variable expressivity, even within affected families. Hematologic malignancies are diagnosed at a median age of 33 years. However, the reported age range for an MDS or leukemia diagnosis is broad (range, 5 y to 76 y).[5]Genetic anticipation (which can lead to disease manifestations occurring at earlier ages in successive generations) has also been described in RUNX1-FPD.[9,10]

More than 200 families with germline RUNX1 pathogenic variants have been described in the literature.[11] However, it is estimated that 5,515 families with RUNX1 pathogenic variants exist worldwide, based on population incidence and a survey conducted by FPD/AML centers of excellence.[12] Importantly, a RUNX1 database (RUNX1db) and registry is now available as a public resource.[13] RUNX1 somatic mutations have been detected in approximately 10% of AML cases, and the vast majority of these variants are somatic in nature. However, some studies have suggested that in an AML cohort, as many as 16% of RUNX1 mutations that were identified by somatic testing could be germline in nature.[14,15]

Phenotypic criteria proposed by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) state that an individual should exhibit at least one of the following to fit the FPD/AML phenotype:[12]

1. Mild to moderate thrombocytopenia with normal platelet size and volume (in the absence of other causative factors like autoimmune- or drug-related thrombocytopenias).
2. Platelet ultra-structural and/or functional defects, including platelet alpha granule secretion defects, platelet dense granule secretion defects, and impaired platelet aggregation.
3. Diagnosis of a hematologic malignancy (most commonly affecting the myeloid lineage and manifesting as AML or MDS, or less frequently involving the lymphoid lineage and manifesting as T-ALL or other cancers).

In addition to thrombocytopenia and hematologic malignancies, RUNX1-FPD may also be associated with the following features: eczema, psoriasis, arthritis, and other autoimmune disorders.[11]

References:

1. Schnittger S, Dicker F, Kern W, et al.: RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 117 (8): 2348-57, 2011.
2. Johns Hopkins University: Online Mendelian Inheritance in Man: Platelet Disorder, Familial, with Associated Myeloid Malignancy; FPDMM. Johns Hopkins University, 2014. Available online. Last accessed October 4, 2023.
3. Weiss HJ, Chervenick PA, Zalusky R, et al.: A familialdefect in platelet function associated with imapired release of adenosine diphosphate. N Engl J Med 281 (23): 1264-70, 1969.
4. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
5. Feurstein S, Drazer MW, Godley LA: Genetic predisposition to leukemia and other hematologic malignancies. Semin Oncol 43 (5): 598-608, 2016.
6. Owen CJ, Toze CL, Koochin A, et al.: Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 112 (12): 4639-45, 2008.
7. Linden T, Schnittger S, Groll AH, et al.: Childhood B-cell precursor acute lymphoblastic leukaemia in a patient with familial thrombocytopenia and RUNX1 mutation. Br J Haematol 151 (5): 528-30, 2010.
8. Shiba N, Hasegawa D, Park MJ, et al.: CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML). Blood 119 (11): 2612-4, 2012.
9. DiFilippo EC, Coltro G, Carr RM, et al.: Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms. Leukemia 34 (9): 2519-2524, 2020.
10. Duarte BKL, Yamaguti-Hayakawa GG, Medina SS, et al.: Longitudinal sequencing of RUNX1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies. Br J Haematol 186 (5): 724-734, 2019.
11. Brown AL, Arts P, Carmichael CL, et al.: RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv 4 (6): 1131-1144, 2020.
12. Luo X, Feurstein S, Mohan S, et al.: ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood Adv 3 (20): 2962-2979, 2019.
13. Homan CC, King-Smith SL, Lawrence DM, et al.: The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy. Haematologica 106 (11): 3004-3007, 2021.
14. Simon L, Spinella JF, Yao CY, et al.: High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML. Blood 135 (21): 1882-1886, 2020.
15. Ernst MPT, Kavelaars FG, Löwenberg B, et al.: RUNX1 germline variants in RUNX1-mutant AML: how frequent? Blood 137 (10): 1428-1431, 2021.

Genetics and Molecular Biology of RUNX1-Familial Platelet Disorder (FPD)

Many of the germline RUNX1pathogenic variants seem to be unique to probands or families.[1] The majority of RUNX1 germline pathogenic variants described in the literature are inherited, and de novo germline RUNX1 variants have been rarely reported.[2,3,4] The following types of germline pathogenic variants have been reported in the RUNX1gene: missense variants, nonsense variants, splice-site variants, single nucleotide variants, small insertions, small deletions, and copy number variants (including intragenic and whole-gene deletions).[3,5,6] Pathogenic variants can happen at any location along the RUNX1 gene, but these variants are most often located within the conserved runt-homology domain (RHD) or the transactivation domain (TAD).[7]

Genomic heterogeneity (in terms of somatic clonal evolution) is common, even among asymptomatic individuals with germline RUNX1 pathogenic variants.[7,8,9] More than 80% of evaluated individuals with RUNX1-FPD demonstrate clonal evolution by age 50 years. Secondary somatic mutations in genes involved in epigenetic regulation (i.e., TET2 and DNMT3A) comprise most mutations identified in individuals with RUNX1-FPD who are undergoing surveillance. These secondary mutations are commonly associated with age-related clonal hematopoiesis. Many individuals with RUNX1-FPD–associated hematologic malignancies have evidence of cytogenetic abnormalities (e.g., trisomy 21, trisomy 8, monosomy 7). These individuals can also have secondary somatic mutations in active signaling pathways (i.e., RAS pathway, KIT pathway) or in tumor suppressor genes (i.e., WT1, PHF6, TP53). Individuals can also have additional somatic mutations in the RUNX1 gene.[10]

Notably, baseline morphological and immunophenotypic abnormalities are often present in the bone marrow of asymptomatic individuals with RUNX1-FPD who do not have myelodysplastic syndrome (MDS)/acute myeloid leukemia.[11,12] These abnormalities can include low-for-age bone marrow cellularity and dysplastic megakaryopoiesis, which is often characterized by small, hypolobated megakaryocytes. When mild dysplasia is already present, it can be a challenge to define when an individual's condition progresses to MDS.

References:

1. Sood R, Kamikubo Y, Liu P: Role of RUNX1 in hematological malignancies. Blood 129 (15): 2070-2082, 2017.
2. Feurstein S, Luo X, Shah M, et al.: Revision of RUNX1 variant curation rules. Blood Adv 6 (16): 4726-4730, 2022.
3. Luo X, Feurstein S, Mohan S, et al.: ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood Adv 3 (20): 2962-2979, 2019.
4. Feurstein S, Drazer MW, Godley LA: Genetic predisposition to leukemia and other hematologic malignancies. Semin Oncol 43 (5): 598-608, 2016.
5. Béri-Dexheimer M, Latger-Cannard V, Philippe C, et al.: Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet 16 (8): 1014-8, 2008.
6. Ouchi-Uchiyama M, Sasahara Y, Kikuchi A, et al.: Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets. Pediatr Blood Cancer 62 (12): 2082-8, 2015.
7. Brown AL, Arts P, Carmichael CL, et al.: RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv 4 (6): 1131-1144, 2020.
8. Churpek JE, Pyrtel K, Kanchi KL, et al.: Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126 (22): 2484-90, 2015.
9. DiFilippo EC, Coltro G, Carr RM, et al.: Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms. Leukemia 34 (9): 2519-2524, 2020.
10. Preudhomme C, Renneville A, Bourdon V, et al.: High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood 113 (22): 5583-7, 2009.
11. Chisholm KM, Denton C, Keel S, et al.: Bone Marrow Morphology Associated With Germline RUNX1 Mutations in Patients With Familial Platelet Disorder With Associated Myeloid Malignancy. Pediatr Dev Pathol 22 (4): 315-328, 2019.
12. Kanagal-Shamanna R, Loghavi S, DiNardo CD, et al.: Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica 102 (10): 1661-1670, 2017.

Management and Prognosis for RUNX1-Familial Platelet Disorder (FPD)

Surveillance recommendations for individuals with RUNX1-FPD are based on expert opinion and typically include blood work (including a complete blood count [CBC] with differential conducted once or twice annually), in addition to a physical exam.[1] A bone marrow evaluation is suggested when an individual is first diagnosed with RUNX1-FPD. It is suggested that bone marrow evaluation be repeated when changes are found in the individual's blood counts or when new, concerning medical findings (such as recurrent infections) occur. While annual bone marrow evaluations are often recommended for research purposes, there are no current clinical or pathological criteria that can reliably predict the development of hematologic malignancies in individuals with RUNX1-FPD.

Clinical outcomes and management decisions for individuals with RUNX1-FPD who experience malignant transformation are rarely reported. In general, standard treatment for the underlying malignancy (i.e., myelodysplastic syndrome, acute myeloid leukemia, or T-cell acute lymphoblastic leukemia directed-therapies) and consideration of an allogeneic stem cell transplant are recommended. Potential related donors should be evaluated for the familial RUNX1pathogenic variant to avoid transplanting stem cells with the same underlying genetic defect whenever possible. This approach can help avoid risks of graft failure and donor-derived leukemias.

References:

1. Churpek JE, Lorenz R, Nedumgottil S, et al.: Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk Lymphoma 54 (1): 28-35, 2013.

Latest Updates to This Summary (12 / 14 / 2023)

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about RUNX1-familial platelet disorder (RUNX1-FPD). It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for RUNX1-Familial Platelet Disorder are:

• Julia Cooper, MS, CGC (Ohio State University)
• Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
• Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

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Last Revised: 2023-12-14