Beyond Pathogenic RUNX1 Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies

Abstract

Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.

Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD

“…Mutations associated with RUNX1-FPD can create non-functional or dominant-negative alleles, [4][5][6][7] with missense mutations mainly clustering in the RUNT homology domain (RHD). 1,49 To study the gene dose effects of Runx1 deficiency and the in vivo consequences of a residual RUNX1 function below 50%, as might be caused by dominant-negative mutations, we crossed Runx1 L148A/+ mice, 5,32,50 harboring a hypomorphic point mutation in the RHD (Figure 1A) with Runx1 +/− mice, 8 generated via an insert that disrupts the RHD by introducing premature stop codons in all reading frames (Figure 1A). Interbreeding these mouse strains resulted in Runx1 +/+ (wild type), Runx1 L148A/+ , Runx1 +/− and Runx1 L148A/− mice.…”

Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome

“…It functions as a transcriptional activator for some genes and a transcriptional repressor for others. Somatic variants in RUNX1 are among the most common variants in adults and children with ALL, AML, or MDS, including recurrent fusions in B-ALL ( ETV6 - RUNX1 ) and AML ( RUNX1 - RUNX1T1 ) [ 41 ]. RUNX1 was identified as a gene located at a truncation site on chromosome 21 in t (8;21), which is found in AML [ 153 ].…”

Platelet genetic testing by next‐generation sequencing: A practical update

“…The affected patients usually have a family history of congenital thrombocytopenia and later onset of hematologic neoplasms. It is worth noting that RUNX1 mutation‐associated thrombocytopenia may have partial penetrant; therefore, genetic testing for possible RUNX1 mutation should be conducted for all family members, despite normal platelet counts 32 …”

“…It is worth noting that RUNX1 mutation-associated thrombocytopenia may have partial penetrant; therefore, genetic testing for possible RUNX1 mutation should be conducted for all family members, despite normal platelet counts. 32 A subgroup of normocytic thrombocytopenias is caused by congenital amegakaryocytic thrombocytopenia. Non-syndromic congenital amegakaryocytic thrombocytopenia is a recessive disorder due to an MPL mutation.…”