Myeloid Neoplasms with Germline RUNX1 Mutation

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Primary Author(s)*

Malini Sathanoori, PhD, FACMG

Pathgroup Labs, Nashville, TN

Cancer Category/Type

Myeloid Neoplasms with Germline Predisposition

Cancer Sub-Classification / Subtype

Myeloid Neoplasms with Germline RUNX1 Mutation

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system within the section of Myeloid Neoplasms with Germline Predisposition[1].

Familial platelet disorder with propensity to myeloid malignancies (FPDMM aka FPD) is an autosomal dominant disorder characterized by quantitative and/or qualitative platelet defects with a tendency to develop a variety of hematological malignancies including MDS/AML. Heterozygous germline mutations in the RUNX1 gene are responsible genetic events for FPD/AML[2][3].

RUNX1 germline mutations cause impaired megakaryopoiesis that gives rise to inherited thrombocytopenia and subsequent acute myeloid leukemia (AML)[4].

Synonyms / Terminology

Familial Platelet Disorder with associated Myeloid Malignancy; FPDMM

Familial platelet disorder with predisposition to acute myelogenous leukemia; FPD/AML

Familial platelet disorder with predisposition to myeloid malignancy

Familial platelet disorder with propensity to acute myeloid leukemia

Familial thrombocytopenia with propensity to acute myelogenous leukemia

Epidemiology / Prevalence

FPD/AML typically manifests in individuals at around 30-40 yrs. of age[2]. The lifetime risk of developing MDS/AML in FPD/AML patients is about 40% as reported in various studies with an average age of onset being 33 years[5]. Although the majority of these patients develop MDS/AML, other types of leukemia such as T-acute lymphoblastic leukemia (T‐ALL)[6], hairy cell leukemia (HCL)[7], and chronic myelomonocytic leukemia (CMML)[8] have been described.

Clinical Features

The clinical presentation of FPDMM is highly variable, even within the same family with heterogeneity in age, presentation and significant risk of MDS/AML transformation estimated at 20–60%[9][10][11]. Patients often present with either personal or family history of mild‐to‐moderate bleeding tendency typically present from childhood. The bleeding tendencies are secondary to thrombocytopenia and/or platelet dysfunction. However, some family members harboring the germline RUNX1 mutation have normal platelet counts, thus escaping the diagnosis of inherited thrombocytopenia (IT)[12].

Sites of Involvement

Blood and bone marrow

Morphologic Features

Bone marrow features in patients with FPDMM may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis[12]. Patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation[13].


Documented reports on flow cytometry findings in FPDMM are limited in the literature. However, two studies[14][15] reported findings on a panel of markers listed in the below table. In general, the histopathological findings in FPDMM is very similar to sporadic AML/MDS at the onset of myeloid malignancy.

Finding Marker
Positive (universal) CD34, CD33
Increased Expression CD13, CD117, CD123
Decreased Expression CD38

Chromosomal Rearrangements (Gene Fusions)

While there are no characteristic chromosome rearrangements associated with FPDMM per se, a few case reports on constitutional rearrangements involving chromosome 21q22 at the RUNX1 gene location have been described in the literature[16][17]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
r(21)(p13q22) Unknown Haploinsufficiency due to loss of RUNX1 gene Case report[16]
t(16;21)(p13;q22) ?/5' RUNX1 Likely haploinsufficiency due to disruption of RUNX1 gene Case report[17]

Characteristic Chromosomal Aberrations / Patterns

Both sporadic and germline RUNX1-mutated AMLs demonstrated a similar frequency of monosomy 7, whereas sporadic RUNX1-mutated AML had an increased frequency of trisomy 8[11].

Genomic Gain/Loss/LOH

Although most of the FPDMM families harbor germline RUNX1 variants, inherited large intragenic duplications/deletions have been also described in these families[10]. In addition, de novo microdeletion 21q22.11~12 as a cause of syndromic thromobocytopenia and predisposition to MDS/AML have been reported in the literature [18][19][20].

Gene Mutations (SNV/INDEL)

Most patients with FPD carry RUNX1 gene point mutations and small indels, that result in missense, nonsense or frame shift changes in the protein. Rarely, larger intragenic deletions and duplications have also been reported. Most often, RUNX1 germline mutations cluster in the runt-homology domain (RHD) and transactivation domain (TAD) [21]. Family studies reported in literature have observed most RUNX1 germline mutations in residues within RHD (AA 105-204) [21][22]. A complete list of known and reported germline mutations can be found in external public databases such as ClinGen [23] and ClinVar.

Other Mutations

Acquisition of second genetic event involving RUNX1 or secondary mutations in other myeloid-related genes is associated with progression to MDS/AML[11]. Studies reported in literature are a small cohort of family studies, and have observed a high frequency of RUNX1 alterations on the other allele as the second hit.

Type Gene/Region/Other
Secondary Mutations RUNX1 (second hit), GATA2, ASXL1, CEBPA, JAK2 [11]

Epigenomics (Methylation)

None at this time

Genes and Main Pathways Involved

RUNX1 is a tumor suppressor gene. It encodes a subunit of the core binding factor (CBF) transcription factor, which regulates expression of several hematopoietic genes. The RUNX1 protein contains a DNA‐binding domain (termed runt homology domain – RHD) and a domain that enables it to dimerize with its partner, CBFB. A variety of mutations in RUNX1 have been described in individual families with FPD/AML, most in the RHD[24]. Individual mutations are thought to result in different degrees of functional loss of the RUNX1 protein and variable phenotypes of the FPD/AML disease between families[3].

Diagnostic Testing Methods

RUNX1 mutations are unique for each FPDMM family with very few recurrent mutations described in literature, making diagnostic molecular testing challenging. Genomic Sequencing of all RUNX1 coding exons is recommended and copy number analysis by whole genome arrays for large deletions and duplications will be useful in such instances when there is a high index of suspicion for a germline mutation and standard testing is negative[12].

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

RUNX1 germline mutation is known to be associated with a long-standing thrombocytopenia. RUNX1 germline mutation by itself is not sufficient to cause hematological neoplasm. Most individuals that carry a germline RUNX1 mutation need additional secondary genetic alteration in either RUNX1 or other myeloid genes to develop hematological neoplasms. Progression to MDS/AML may be associated with bi‐ or pancytopenia, multilineage dysplasia, acquisition of cytogenetic abnormalities, or somatic mutations indicating clonal progression, and/or bi‐allelic mutations in RUNX1, ANKRD26, or ETV6[12].

Currently there is no specific targeted therapy for RUNX1 germline mutation. However, the curative therapy of choice for many of the myeloid neoplasms with germline predisposition is an allogeneic HSCT[25]. There is mounting evidence that preemptive allogeneic hematopoietic stem-cell transplantation (pHSCT) can improve overall outcomes [26].

Familial Forms

Familial platelet disorder with predisposition to acute myelogenous leukemia; FPD/AML

Other Information

Genetic counseling is an important consequence of the identification of RUNX1 germline mutation. Equally important is choosing appropriate treatment regimens and genetic screening of potential‐related donors for HSCT to avoid using a mutation positive‐related donor and subsequent donor‐derived MDS/AML or other hematologic malignancy[10][12][27].

Individuals carrying homozygous RUNX1 mutations, bi-allelic RUNX1 mutations in trans (compound heterozygous RUNX1 mutations), RUNX1 mutations at heterozygous allele frequency of 50%, and trisomy 21 may indicate that those individuals are likely to carry germline RUNX1 variants causing FPDMM [28].



Platelet Disorder, Familial, With Associated Myeloid Malignancy; FPDMM





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*Citation of this Page: Sathanoori M. “Myeloid Neoplasms with Germline RUNX1 Mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 04/28/2021, Neoplasms with Germline RUNX1 Mutation.