C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies

Kozubík, Kateřina Staňo; Radová, Lenka; Pešová, Michaela; Réblová, Kamila; Trizuljak, Jakub; Plevová, Karla; Fiamoli, Veronika; Gumulec, Jaromír; Urbánková, Helena; Szotkowski, Tomáš; Mayer, Jiřı́; Pospı́šilová, Šárka; Doubek, Michael

doi:10.1007/s12185-018-2514-3

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…62 Coincidental BCOR and BCORL1 deleterious mutations were suggested to play a role (together with PHF6 mutation) in the leukemic transformation of a patient with familial platelet disorder related to germinal C-terminal RUNX1 mutation. 64 Thus, occurrence of BCOR and BCORL1 mutations in the same tumor suggest the they may not be redundant, consistently with the likely different function of the 2 proteins.…”

Section: Amlmentioning

confidence: 91%

BCORgene alterations in hematologic diseases

Sportoletti

Sorcini

Falini

2021

Blood

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The BCL6 co-repressor (BCOR) is a transcription factor involved in the control of embryogenesis, mesenchymal stem cells function, hematopoiesis and lymphoid development. Recurrent somatic clonal mutations of the BCOR gene and its homologue BCORL1 have been detected in several hematological malignancies and aplastic anemia. They are scattered across the whole gene length and mostly represent frameshifts (deletions, insertions), nonsense and missence mutations. These disruptive events lead to the loss of full-length BCOR protein and to the lack or low expression of a truncated form of the protein, both consistent with the tumor suppressor role of BCOR. BCOR and BCORL1 mutations are similar to those causing two rare X-linked diseases: the oculo-facio-cardio-dental (OFCD) and the Shukla-Vernon syndromes, respectively. Here, we focus on the structure and function of normal BCOR and BCORL1 in normal hematopoietic and lymphoid tissues and review the frequency and clinical significance of the mutations of these genes in malignant and non-malignant hematological diseases. Moreover, we discuss the importance of mouse models to better understand the role of Bcor loss, alone and combined with alterations of other genes (e.g. Dnmt3a and Tet2), in promoting hematological malignancies and in providing a useful platform for the development of new targeted therapies.

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Section: Amlmentioning

confidence: 91%

BCORgene alterations in hematologic diseases

Sportoletti

Sorcini

Falini

2021

Blood

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“…Interestingly, a case report of AML with MRC harboring a P2RY8-CRLF2 fusion was found to have gained a PHF6 mutation upon transformation to AML, suggesting a potential role for PHF6 in the transition of MDS to AML (55). Further evidence for PHF6 mutations acquired secondarily and leading to progression of myeloid neoplasms was found in patients with germline mutations of RUNX1, where PHF6 mutations were implicated in the transition to MDS in one patient and the transition to AML in the other (56,57). Interestingly, PHF6 has been shown to frequently co-occur with RUNX1 in AML (58).…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

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“…Comprehensive evaluation involves a thorough review of individual's family and personal history, hematologic investigation, and personal risk assessment of likelihood of a hereditary predisposition within his/her family, and if necessary, genetic testing with NGS to determine the possibility of a germline mutation should be offered [13]. We provide an example of a familial case of FDPMM in Figure 2 [14].…”

Section: Diagnostic Criteria To Identify At-risk Individualsmentioning

confidence: 99%

“…One of the affected individuals developed myelodysplastic syndrome, which progressed to acute myelogenous leukemia. Platelet count (PLT) reported in ×109/L, samples analyzed by exome sequencing marked with an asterisk (*), age of death if known [14].…”

Section: Phenotype/genotype Correlationmentioning

confidence: 99%

Familial Leukemia Associated with Thrombocytopenia

Trizuljak¹,

Doubek²

2019

Germ Line Mutations Associated Leukemia

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Familial predisposition to leukemia has been known for decades. In some families, this condition is also associated with thrombocytopenia and history of bleeding. Germline mutations in the RUNX1 gene have been proven to cause familial platelet disorder with predisposition to myeloid malignancies (FDPMM). The disease typically presents with mild-to-moderate thrombocytopenia with normal-size platelets, functional platelet defects leading to prolonged bleeding, and an increased risk to develop myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or T-cell acute lymphoblastic leukemia (T-ALL). In recent years, molecular defects in other genes, such as ANKRD26 and ETV6, have been associated with thrombocytopenia and susceptibility to hematological malignancy as well. In our chapter, we will present a review of up-to-date knowledge on this topic along with several case studies demonstrating the diagnostic process and management of the affected families.

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C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies

Cited by 8 publications

References 23 publications

BCORgene alterations in hematologic diseases

BCORgene alterations in hematologic diseases

PHF6 Mutations in Hematologic Malignancies

Familial Leukemia Associated with Thrombocytopenia

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