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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)
Brigitte Schlegelberger1, Paula G Heller2
1Department of Human Genetics, Hannover Medical School, Hannover, Germany.
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 presents 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 myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or T-cell acute lymphoblastic leukemia (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 induce pluripotent stem cells (iPSC) lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.
Insights
Germline RUNX1 mutations cause familial platelet disorder with leukemia predisposition. Gene correction in patient-derived stem cells shows potential to reverse disease phenotypes, offering new therapeutic avenues.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- RUNX1 is a master regulator of hematopoietic differentiation.
- Germline mutations in RUNX1 cause Familial Platelet Disorder with predisposition to Myeloid Leukemia (FPDMM).
- FPDMM is characterized by thrombocytopenia, platelet dysfunction, and increased risk of hematological neoplasms like MDS, AML, and T-ALL.
Purpose of the Study:
- To review disease-causing alterations of RUNX1.
- To discuss the clinical presentation and genetic basis of FPDMM.
- To explore potential therapeutic strategies for FPDMM.
Main Methods:
- Review of existing literature on RUNX1 mutations and FPDMM.
- Analysis of the molecular mechanisms underlying FPDMM pathogenesis.
- Exploration of gene correction strategies using induced pluripotent stem cells (iPSCs).
Main Results:
- Germline RUNX1 mutations lead to FPDMM, requiring secondary mutations for hematological neoplasms.
- Hematopoietic stem cell transplantation from carriers of familial mutations should be avoided.
- Gene correction of RUNX1 in patient-derived iPSCs shows promise in reversing FPDMM phenotype.
Conclusions:
- RUNX1 mutations are critical in FPDMM development and leukemia predisposition.
- Genetic counseling and careful donor selection are crucial for FPDMM families.
- Gene correction offers a potential future therapy for FPDMM.
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