RUNX1 – risk management

Monoallelic germline pathogenic variants in RUNX1 cause autosomal dominant familial platelet disorder with predisposition to myeloid malignancy (FPDMM).^r The characteristic features include the following, although there is significant phenotypic heterogeneity:

1. Lifelong mild-to-moderate thrombocytopenia
2. Functional platelet defects leading to prolonged bleeding
3. Increased risk of haematologic neoplasms, most commonly myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) 
4. Non-haematological features: increased risk of atopy and gastrointestinal tract motility disorders.

The care of an individual who has developed a related malignancy should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Unaffected known or obligate RUNX1 pathogenic variant carriers^{^}

Exclusion criteria

• Individuals with RUNX1 pathogenic variants in neoplastic tissue only
• Individuals with RUNX1 variants of uncertain significance

^ Refer to the evidence section for information about the selection of appropriate samples for testing RUNX1 germline pathogenic variants.

Abbreviations: MDS – myelodysplastic syndromes; AML – acute myeloid leukaemia; ALL – acute lymphoblastic leukaemia
^* Source: Australian Institute of Health and Welfare (AIHW) 2024 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2020 data, unadjusted for competing mortality)
^** Includes myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) 

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on general cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Abbreviation: MDS – myelodysplastic syndrome

The management of the non-malignant features of FPDMM is outside the scope of this document. Where available, management by a multidisciplinary team with knowledge of FPDMM is recommended. Individuals with a monoallelic RUNX1 germline pathogenic variant should be informed of the risk of platelet dysfunction and management options, particularly during pregnancy and major surgery.

There is no agreed protocol for the management of RUNX1 germline pathogenic variant carriers who have not developed haematological neoplasm. ^rrrr The recommendations in this protocol are based on expert opinion.

There is significant clinical heterogeneity in patients with FPDMM. Almost all will develop some degree of abnormal bleeding due to platelet deficiencies. However, there is inter- and intra-familial phenotypic variability and up to 9% have normal platelet counts.^r Bleeding abnormalities may include epistaxis, easy bruising, excessive bleeding during minor surgery or injuries, and/or menorrhagia. Age of onset can range from infancy to late adulthood.

Approximately 62% of families have at least one individual with a haematological malignancy, most commonly MDS and AML.^rr More rarely, other types of leukaemia, including B-cell ALL, hairy cell leukaemia, and chronic myelomonocytic leukaemia, and lymphomas have been reported.^rr The median age of onset for haematological malignancy is 33 years.^r  

Skin findings, including eczema and psoriasis, have been reported in up to 30-50% of individuals with FPDMM and can be treated topically.  An increased frequency of other atopic and autoimmune disorders have been reported, although requires further investigation.^r Gastrointestinal tract motility disorders including gastroesophageal reflux and constipation are also more prevalent in FPDMM.^r

For individuals with FPDMM who develop haematological malignancy, initial management is determined by the standard of care for the particular diagnosis.

Testing for RUNX1 germline pathogenic variants

In peripheral blood, somatic genetic rescue (SGR) can lead to loss of a RUNX1 germline pathogenic variant from white blood cell DNA. Saliva and buccal cell specimens can be contaminated with white blood cells and are not reliable for detection of a RUNX1 germline pathogenic variant. Cultured skin fibroblasts from a skin punch biopsy, or DNA extracted from hair bulbs, are the preferred tissue specimens for diagnostic germline testing for RUNX1 pathogenic variants.^r For predictive testing of unaffected individuals, a peripheral blood sample may be used.

Haematological malignancy/neoplasia

If haematopoietic stem cell transplantation (HSCT) is planned, genetic testing of relatives who are potential donors is recommended to avoid HSCT from a relative who has inherited the familial RUNX1 pathogenic variant, as this has been associated with poor donor and recipient outcome.^r

Surveillance

There is no evidence of benefit of surveillance by periodic FBE, but this is a low-risk procedure and has the potential to detect peripheral blood abnormalities prior to onset of obvious symptoms.^r

Bone marrow biopsy has the potential to detect malignant transformation prior to the onset of symptoms. However, this is an invasive procedure, there is incomplete penetrance for haematological malignancy (see Lifetime risk of cancer) and there is lack of evidence for a beneficial effect of baseline and/or periodic bone marrow biopsy on neoplasia-related morbidity and mortality. Baseline bone marrow biopsy should be considered with a repeat bone marrow biopsy/aspiration in the presence of persistent unexplained FBE anomalies. 

Asymptomatic carriers of RUNX1 germline pathogenic variants develop detectable clonal haematopoiesis prior to malignant transformation (cumulative risk of up to 80% by age 50 years).^r  Next generation sequencing to detect clonal haematopoiesis in cells from peripheral blood or bone marrow has the potential to prospectively identify RUNX1 carriers at higher risk for evolution to MDS/AML, however the clinical utility is unproven.

Other approaches

There is no evidence to support prophylactic/pre-emptive HSCT in RUNX1 germline pathogenic variant carriers who have not developed a haematological neoplasm.

Thrombocytopenia and platelet dysfunction

Almost all RUNX1 germline pathogenic variant carriers have a functional platelet defect and most have thrombocytopenia, which is usually mild to moderate.^rr Antifibrinolytic agents or desmopressin may be considered in some circumstances, e.g., history of mild to moderate bleeding and planned surgical procedure or childbirth. To minimise the risk of alloimmunisation, platelet transfusions should only be used in individuals with severe bleeding.

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Bibliography

Difilippo, E. C., G. Coltro, R. M. Carr, et al. 2020. "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.

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Heller, P. G., A. C. Glembotsky, M. J. Gandhi, et al. 2005. "Low mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel aml1 mutation." Blood 105(12): 4664-4670.

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Germ-line heterozygous mutations in the hematopoietic transcription factor AML1 (RUNX1) have been identified in patients with familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML), which is characterized by thrombocytopenia, abnormal platelet function, and propensity to myeloid malignancies. We identified a novel mutation in the AML1 gene in an FPD/AML pedigree characterized by a single nucleotide deletion that generates a frameshift and premature chain termination (Pro218fs-Ter225). Both wild-type and mutant transcripts were expressed in affected individuals by allele-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Thrombopoietin (TPO) binds to the Mpl receptor and is the major regulator of megakaryopoiesis. To explore the mechanisms underlying thrombocytopenia, we studied the TPO/Mpl pathway in this newly identified pedigree. TPO levels were mildly to moderately elevated. On flow cytometry and immunoblotting, Mpl receptor expression was decreased and TPO-induced signaling was impaired. While no mutations were identified in the MPL gene by sequence analysis, low MPL mRNA levels were found, suggesting decreased gene expression. Of particular interest, several AML1-binding motifs are present in the MPL promoter, suggesting MPL is an AML1 target. In conclusion, we identified a C-terminal AML1 mutation that leads to a decrease in Mpl receptor expression, providing a potential explanation for thrombocytopenia in this FPD/AML pedigree.

Sacco, K., K. Laky, M. Li, et al. 2021. "Germline RUNX1 deficiency predisposes to allergy and autoimmunity" J allergy clin immunol. 147(2) Supplement

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Rationale
The Runx1 transcription factor decreases GATA3 and IL-4 expression and Th2 skewing and promotes Th1/Th17/Tregulatory (Treg) cell development and function. We hypothesized that patients with germline RUNX1 deficiency would be predisposed to allergic and/or autoimmune disease.

Methods
Thirty-one patients (17 female; median age 42 years, range 2-74) with confirmed RUNX1 mutations were evaluated. Peripheral blood was obtained to evaluate hematologic variables, total and allergen specific IgE, and lymphocyte immune phenotypes.

Results
29/31 patients had a positive allergic history; 21 had allergic rhinitis, 16 allergic conjunctivitis, and 20 mild-moderate eczema controlled with topical glucocorticoids and emollients. Seven patients had doctor-diagnosed asthma with 1 patient receiving mepolizumab for eosinophilic asthma. Four reported oral allergy syndrome. Two patients had IgE-mediated food allergy to flounder and egg, respectively, and two had biopsy-proven eosinophilic esophagitis. Five patients reported autoimmune disorders including mixed connective tissue disease, Hashimoto’s thyroiditis, Sjogren’s syndrome, alopecia universalis and systemic Juvenile idiopathic arthritis. Median total IgE and eosinophil counts were within the normal range (73.35 IU/mL; range 16 – 635 IU/mL and 215/mcL; range 0-1000/mcL, respectively). Median CD4 and CD8 T cells counts were within the normal range, although patients exhibited an increased frequency of memory CD4+ T cells, decreased CD4:CD8 ratios, and decreased Tregs in peripheral blood when compared to healthy controls.

Conclusions
Patients with germline RUNX1 deficiency exhibit an increased prevalence of atopic and autoimmune disorders, demonstrating an important role for Runx1 in tolerance development in humans.

Shiba, N., D. Hasegawa, M. J. Park, et al. 2012. "CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML)." Blood 119(11): 2612-2614.

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Familial platelet disorder with a propensity to develop acute myeloid leukemia (FPD/AML) is a rare autosomal dominant disease characterized by thrombocytopenia, abnormal platelet function, and a propensity to develop myelodysplastic syndrome (MDS) and AML. So far, > 20 affected families have been reported. Recently, a second RUNX1 alteration has been reported; however, no additional molecular abnormalities have been found so far. We identified an acquired CBL mutation and 11q-acquired uniparental disomy (11q-aUPD) in a patient with chronic myelomonocytic leukemia (CMML) secondary to FPD with RUNX1 mutation but not in the same patient during refractory cytopenia. This finding suggests that alterations of the CBL gene and RUNX1 gene may cooperate in the pathogenesis of CMML in patients with FPD/AML. The presence of CBL mutations and 11q-aUPD was an important "second hit" that could be an indicator of leukemic transformation of MDS or AML in patients with FPD/AML.

Six, K. A., U. Gerdemann, A. L. Brown, et al. 2021. "B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations." Blood Adv 5(16): 3199-3202.

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Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C>T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic sample. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.

Toya, T., A. Yoshimi, T. Morioka, et al. 2014. "Development of hairy cell leukemia in familial platelet disorder with predisposition to acute myeloid leukemia." Platelets 25(4): 300-302.

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Abstract Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disorder characterized by mild to moderate thrombocytopenia with or without its impaired function, inherited RUNX1 mutation and high incidence of myeloid malignancy, such as myelodysplastic syndrome or acute myeloid leukemia. A 72-year-old male visited our institute because of gradually progressive pancytopenia and splenomegaly, and was diagnosed as having hairy cell leukemia. He was administered one course of intravenous cladribine (0.12 mg/kg, day 1-5) and achieved hematological complete response. Mutation analyses of RUNX1 gene were underwent because familial history of hematological malignancies evoked a possibility of FPD/AML. As a result, RUNX1 L445P mutation was identified in the peripheral blood and the mutation was considered as germ-line mutation because the same mutation was detected in the buccal mucosa. BRAF V600E mutation was also identified in the peripheral blood but not in the buccal mucosa. To our knowledge, this is the first report of B cell malignancy arising from FPD/AML.

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