RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Abstract

In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL.Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into iPSC lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.  Definition of RUNX1 deficiency/ FPDMMRUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e. t(12;21)/RUNX1/ETV6 in pediatric acute lymphoblastic leukemia, t(8;21)/RUNX1/RUNX1T1 in acute myeloid leukemia (AML), and t(3;21)/RUNX1/EVI1 in therapy-related AML or chronic myeloid leukemia in blast phase [2,3]. Moreover, somatic RUNX1 mutations have recently been identified as recurrent abnormalities in myelodysplastic syndromes (MDS) and AML [4]. These somatic changes are associated with poor prognosis in AML and MDS indicating an increased resistance against exposure to genotoxic agents. RUNX1 mutations seem to trigger progression into MDS and AML in Fanconi anemia and severe congenital neutropenia [5,6]. Song et al. (1999) were the first to describe heterozygous germline RUNX1 mutations in six families, each carrying a different mutation. Individuals carrying germline RUNX1 may be asymptomatic throughout lifetime or develop familial platelet disorder with myeloid malignancies (i.e. FPDMM, OMIM 601399). Characteristic features are 1) mild to moderate thrombocytopenia; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. There is a great phenotypic heterogeneity. FPDMM is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.  Diagnostic criteria to identify persons at riskSince the diagnosis of FPDMM in a patient with leukemia carries important critical implications for the patient and also for her/his family, it is important to recognize clinical features pointing to this genetic predisposition [7]. An important clinical feature is persisting thrombocytopenia or aspirin-like platelet disorder, which are not explained by other reasons.Thorough pedigree analysis may identify first or second degree relatives with bleeding tendency or hematological neoplasms. It has to be kept i...

The evolving role of next generation sequencing in myelodysplastic syndromes

“…Studies have linked germline mutations in GATA2 , RUNX1 , ETV6 and DDX41, among other selected genes, with a predisposition to MDS and AML (Bannon & DiNardo, ; Sperling et al , ). RUNX1 germline mutations have been associated with FPDMM with a median age of onset of MDS/AML of 33 years (Owen et al , ; Schlegelberger & Heller, ). Patients with germline GATA2 haploinsufficency have a 50% risk of MDS/AML and often present with unilineage cytopenia, nontuberculous mycobacterial and viral infections, and monosomy 7 or trisomy 8 karyotypic abnormalities (Babushok et al , ).…”

Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia

“…The mean platelet volume by automated method and platelet size on microscopic examination is normal. On the May‐Grunwald‐Giemsa stained peripheral blood smear examination, platelets reveal normal morphology or may have a gray appearance due to reduction in alpha granules. In a study by Kanagal‐Shamanna et al peripheral blood smears in a subset of FPD/AML patients with myeloid neoplasm revealed mild platelet anisocytosis and abnormalities in platelet granulation, namely hypo‐ or agranulation, along with red cell macrocytosis and cytoplasmic hypogranulation and abnormal nuclear segmentation in granulocytes.…”

“…Dysmorphic megakaryocytes are a consistent finding (Figure 1), present even prior to MDS or leukemic transformation and accounting for more than 10% of the megakaryocytes in the majority of cases. 40,41 Small forms with scant cytoplasm and nuclear hypolobation, with asynchronous nuclear-cytoplasmic maturation and micromegakaryocytes, are common 40,42 in the absence of MDS/AML. Bone marrow eosinophilia has been frequently noted.…”

Pediatric leukemia susceptibility disorders: manifestations and management

“…In addition, genetic anticipation in families with RUNX1 germline pathogenic variants has been reported; thus, family members should be counseled and closely monitored after the diagnosis of an RUNX1 mutation in a patient. 26 Schlegelberger and Heller 26 recommend regular clinical examinations including a complete blood count (CBC) with differential and a yearly bone marrow examination, with counseling regarding the signs and symptoms of leukemia.…”