scholarly journals A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder

Platelets ◽  
2021 ◽  
pp. 1-4
Author(s):  
Ibrahim Almazni ◽  
Pavel Chudakou ◽  
Alison Dawson-Meadows ◽  
Kate Downes ◽  
Kathleen Freson ◽  
...  
Keyword(s):  
Platelet Disorder ◽  
Familial Platelet Disorder

Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3565-3572 ◽  
Author(s):  
Weili Sun ◽  
James R. Downing
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Normal Limits ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Transcriptional Complex

The AML1/CBFβ transcriptional complex is essential for the formation of definitive hematopoietic stem cells (HSCs). Moreover, development of the hematopoietic system is exquisitely sensitive to the level of this complex. To investigate the effect of AML1 dosage on adult hematopoiesis, we compared the hematopoietic systems of AML1+/– and AML1+/+ mice. Surprisingly, loss of a single AML1 allele resulted in a 50% reduction in long-term repopulating hematopoietic stem cells (LTR-HSCs). This decrease did not, however, extend to the next level of hematopoietic differentiation. Instead, AML1+/– mice had an increase in multilineage progenitors, an expansion that resulted in enhanced engraftment following transplantation. The expanded pool of AML1+/– progenitors remained responsive to homeostatic mechanisms and thus the number of mature cells in most lineages remained within normal limits. Two notable exceptions were a decrease in CD4+ T cells, leading to an inversion of the CD4+ to CD8+ T-cell ratio and a decrease in circulating platelets. These data demonstrate a dosage-dependent role for AML1/CBFβ in regulating the quantity of HSCs and their downstream committed progenitors, as well as a more restricted role in T cells and platelets. The latter defect mimics one of the key abnormalities in human patients with the familial platelet disorder resulting from AML1 haploinsufficiency.

scholarly journals Detection of an Abnormal Myeloid Clone by Flow Cytometry in Familial Platelet Disorder With Propensity to Myeloid Malignancy

2016 ◽  
Vol 145 (2) ◽  
pp. 271-276 ◽  
Author(s):  
Chi Young Ok ◽  
Vasiliki Leventaki ◽  
Sa A. Wang ◽  
Courtney Dinardo ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Malignancy ◽  
Platelet Disorder ◽  
Familial Platelet Disorder

scholarly journals RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

2020 ◽  
Vol 4 (6) ◽  
pp. 1131-1144 ◽  
Author(s):  
Anna L. Brown ◽  
Peer Arts ◽  
Catherine L. Carmichael ◽  
Milena Babic ◽  
Julia Dobbins ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Published Data ◽  
Data Sets ◽  
Gene Deletions ◽  
Phenotypic Differences ◽  
Recurrent Mutations ◽  
Platelet Disorder ◽  
Related Transcription Factor ◽  
Phenotype Heterogeneity ◽  
Familial Platelet Disorder

Abstract First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

scholarly journals MYH10 protein expression in platelets as a biomarker of RUNX1 and FLI1 alterations

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2719-2722 ◽  
Author(s):  
Iléana Antony-Debré ◽  
Dominique Bluteau ◽  
Raphael Itzykson ◽  
Véronique Baccini ◽  
Aline Renneville ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematologic Malignancies ◽  
Chronic Myelomonocytic Leukemia ◽  
Secondary Acute Myeloid Leukemia ◽  
Platelet Disorder ◽  
Associated Proteins ◽  
Familial Platelet Disorder ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Abstract RUNX1 gene alterations are associated with acquired and inherited hematologic malignancies that include familial platelet disorder/acute myeloid leukemia, primary or secondary acute myeloid leukemia, and chronic myelomonocytic leukemia. Recently, we reported that RUNX1-mediated silencing of nonmuscle myosin heavy chain IIB (MYH10) was required for megakaryocyte ploidization and maturation. Here we demonstrate that runx1 deletion in mice induces the persistence of MYH10 in platelets, and a similar persistence was observed in platelets of patients with constitutional (familial platelet disorder/acute myeloid leukemia) or acquired (chronic myelomonocytic leukemia) RUNX1 mutations. MYH10 was also detected in platelets of patients with the Paris-Trousseau syndrome, a thrombocytopenia related to the deletion of the transcription factor FLI1 that forms a complex with RUNX1 to regulate megakaryopoiesis, whereas MYH10 persistence was not observed in other inherited forms of thrombocytopenia. We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins.

Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6310-6320 ◽  
Author(s):  
Dominique Bluteau ◽  
Laure Gilles ◽  
Morgane Hilpert ◽  
Iléana Antony-Debré ◽  
Chloe James ◽  
...  
Keyword(s):  
Regulatory Gene ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Down Regulation ◽  
Α Subunit ◽  
Runx1 Gene ◽  
Platelet Disorder ◽  
Clonogenic Potential ◽  
Acute Myelogenous ◽  
Familial Platelet Disorder

Abstract RUNX1 encodes a DNA-binding α subunit of the core-binding factor, a heterodimeric transcription factor. RUNX1 is a master regulatory gene in hematopoiesis and its disruption is one of the most common aberrations in acute leukemia. Inactivating or dominant-negative mutations in the RUNX1 gene have been also identified in pedigrees of familial platelet disorders with a variable propensity to develop acute myeloid leukemia (FPD/AML). We performed analysis of hematopoiesis from 2 FPD/AML pedigrees with 2 distinct RUNX1 germline mutations, that is, the R139X in a pedigree without AML and the R174Q mutation in a pedigree with AML. Both mutations induced a marked increase in the clonogenic potential of immature CD34+CD38− progenitors, with some self-renewal capacities observed only for R174Q mutation. This increased proliferation correlated with reduction in the expression of NR4A3, a gene previously implicated in leukemia development. We demonstrated that NR4A3 was a direct target of RUNX1 and that restoration of NR4A3 expression partially reduced the clonogenic potential of patient progenitors. We propose that the down-regulation of NR4A3 in RUNX1-mutated hematopoietic progenitors leads to an increase in the pool of cells susceptible to be hit by secondary leukemic genetic events.

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