Decoding RUNX1 Mutations: Exploring the Spectrum of Clinical Outcomes in Blood Disorders

By Nucleati Team
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Germline mutations in the RUNX1 gene are associated with a rare autosomal dominant disorder known as Familial Platelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD/AML). This disorder is characterized by a predisposition to developing AML, thrombocytopenia, and/or abnormal platelet function. Several germline mutations in the RUNX1 gene have been reported to date, and these mutations are often associated with acquired somatic mutations in other genes that drive leukemia development. Additionally, extramedullary disease (EM) is a frequent complication of AML patients with RUNX1 mutations, which is often aggressive and resistant to treatment. Using Nucleati Germline Cancer Evidence Base, we identified case reports describing RUNX1 mutation. From 18 hits, RUNX1 was identified to be mutated in 10 reports. Here, we have described patients from those case reports and highlighted their clinical characteristics, including age, sex, ethnicity, and specific RUNX1 variants, along with their extramedullary and other clinical manifestations.

Case reports

PMID: 12060124

  • Patient/Family information: Family with autosomal dominant inheritance of thrombocytopenia. 
  • Gene/Variation: RUNX1 germline point mutation (p.Ala107Pro). 
  • Clinical Characteristics: Thrombocytopenia prevalent in family; one member developed acute myeloid leukemia.

PMID: 20549580

  • Patient/Family information: Family with FPD and germ-line hemi-allelic mutation Arg174Ter in RUNX1 gene. 
  • Gene/Variation: RUNX1 gene mutation Arg174Ter. 
  • Clinical Characteristics: Proband developed AML, son had T cell lineage ALL with translocation t(1;7)(p34.1;q22).

PMID: 24853048 

  • Patient/Family information: Patient with platelet disorder and family. 
  • Gene/Variation: Novel RUNX1 mutation c.419G>A (p.Ser140Asn) identified in patient and neonate. 
  • Clinical Characteristics: Successful pregnancy, delivery; risk of myelodysplasia and/or acute myeloid leukemia.

PMID: 29666006 

  • Patient/Family information: Two brothers with hematological malignancies, family history of leukemia, low platelet counts in siblings. 
  • Gene/Variation: RUNX1 microdeletion encompassing exons 1-2. 
  • Clinical Characteristics: One brother developed AML, the other T-cell lymphoblastic lymphoma.

PMID: 30083851 

  • Patient/Family information: Family with platelet disorder and predisposition to myeloid malignancies. 
  • Gene/Variation: RUNX1 mutation c.866delG (p.Gly289Aspfs*22). 
  • Clinical Characteristics: One affected individual developed MDS, progressing to AML with additional PHF6, BCORL1, and BCOR gene variants.

PMID: 33292606 

  • Patient/Family information: 58-year-old patient resistant to intensive chemotherapy. Gene/Variation: RUNX1, IDH1, DNMT3A, and NRAS mutations. Clinical Characteristics: Refractory AML, leukemia cutis; unresponsive to venetoclax plus 5-azacytidine treatment.

PMID: 32990483

  • Patient/Family information: Two new kindreds with novel RUNX1 pathogenic variants. 
  • Gene/Variation: Family 1: RUNX1 c.501delT (p.Ser167Argfs*9); Family 2: RUNX1 heterozygous intragenic deletion encompassing exon 5. 
  • Clinical Characteristics: Family 1: Daughter with features resembling juvenile myelomonocytic leukemia, mother with hypoplastic anemia; Family 2: Proband with thrombocytopenia alone, father with increased bruising.

PMID: 24353905

  • Patient/Family information: Family with FPDMM due to a novel RUNX1 mutation (Leu472Ter). 
  • Gene/Variation: RUNX1 Leu472Ter mutation. 
  • Clinical Characteristics: Mutation tracks with thrombocytopenia, acute leukemia, and eczema; the Leu472Ter mutation produces a stably expressed RUNX1 protein product with a decrease in wild-type RUNX1 expression.

PMID: 29780592 

  • Patient/Family info: 27-year-old Malay woman with AML, father & 3 brothers with hereditary thrombocytopenia. 
  • Gene/Variation: Germline RUNX1 mutation, multiple other mutations. 
  • Clinical Characteristics: RUNX1 mutation involved in AML transformation; 5 mutations persisted post-treatment, likely part of preleukemic clone.

PMID: 36502796

  • Patient/Family info: 9-year-old child with B-ALL & constitutional ring chromosome 21. 
  • Gene/Variation: iAMP21 involving RUNX1 gene. 
  • Clinical Characteristics: Constitutional ring chromosome 21 confers risk for B-ALL with iAMP21; germline analysis recommended for iAMP21-related B-ALL.

PMID: 36050938

  • Patient/Family info: AML patient with extramedullary manifestations. 
  • Gene/Variation: Frameshift RUNX1 mutation (c.497_498insGA) in EM sites, ASXL1 point mutation (c.3306G>T) in retroperitoneal tumor. 
  • Clinical Characteristics: Molecular profiling of EM crucial for treatment; 18FDG-PET-imaging needed for detecting residual disease and treatment response.

In conclusion, the patients described in these reports all harbor germline (and/or somatic mutations) in the RUNX1 gene, resulting in various hematologic disorders such as familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21). In addition, several of these patients exhibited extramedullary manifestations (EMs), which are associated with aggressive and resistant disease. The molecular characterization of these patients highlights the importance of continuous molecular profiling and surveillance for detecting differential molecular composition of EM and BM-derived AML, and for assessing treatment response in cases of EM AML. Further studies are necessary to establish the prevalence and prognostic significance of pre-leukemic and secondary mutations in the larger FPD/AML patient cohort, and to elucidate the molecular mechanisms of iAMP21 formation.


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