Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis

Skokowa, Julia; Steinemann, Doris; Katsman-Kuipers, Jenny E.; Zeidler, Cornelia; Klimenkova, Olga; Klimiankou, Maksim; Ünalan, Murat; Kandabarau, Siarhei; Makaryan, Vahagn; Beekman, Renée; Behrens, Kira; Stocking, Carol; Obenauer, Julia; Schnittger, Susanne; Kohlmann, Alexander; Valkhof, Marijke; Hoogenboezem, Remco M.; Göhring, Gudrun; Reinhardt, Dirk; Schlegelberger, Brigitte; Stanulla, Martin; Vandenberghe, Peter; Donadieu, Jean; Zwaan, C. Michel; Touw, Ivo P.; Heuvel‐Eibrink, Marry M. van den; Dale, David C.; Welte, Karl

doi:10.1182/blood-2013-11-538025

Cited by 133 publications

(160 citation statements)

References 44 publications

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“…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.…”

Section:  Definition Of Runx1 Deficiency/ Fpdmmmentioning

confidence: 99%

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

Schlegelberger

Heller

2017

Seminars in Hematology

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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...

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Section:  Definition Of Runx1 Deficiency/ Fpdmmmentioning

confidence: 99%

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

Schlegelberger

Heller

2017

Seminars in Hematology

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“…Possible causes of cytopenia in PIDs comprise cellular or humoral autoimmunity, immune dysregulation in form of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure and myelodysplasia, or secondary myelosuppression. In some patients, cytopenia may be detected as an incidental finding, whereas other patients may be severely ill. Because primary defects in the number or function of phagocytes are classified under their own group of PIDs, 3 the syndromes of severe congenital neutropenia (based on defects in ELANE, GFI1, HAX1, G6PC3, VPS45, and CSFR3 genes, or activating mutations in the Wiskott-Aldrich syndrome [WAS] gene) [4][5][6] and cytopenia-linked metabolic diseases are not included in this overview. Similarly, isolated lymphopenia syndromes are excluded if they present without neutropenia, anemia, or thrombocytopenia; also excluded are non-PID inherited bone marrow failure syndromes such as Fanconi anemia, congenital amegakaryocytic thrombocytopenia, bone marrow failure with radioulnar synostosis, and others (Table 1 and footnotes).…”

Section: Introductionmentioning

confidence: 99%

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Seidel

2014

Blood

124

137

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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“…In families with frequent and childhood onset of leukaemia, regular bone marrow aspirates can be discussed. In future, it might be worth evaluating whether deep or targetedsequencing approaches can be used to detect evolving leukaemic clones 8,9,14 and warrant haematopoietic stem cell transplantation prior to overt leukaemia.…”

Section: Will the Results Of A Genetic Test Influence Lifestyle And Prmentioning

confidence: 99%

Clinical utility gene card for: Familial platelet disorder with associated myeloid malignancies

et al. 2016

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Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis

Cited by 133 publications

References 44 publications

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

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

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Clinical utility gene card for: Familial platelet disorder with associated myeloid malignancies

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