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Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia.

ABSTRACT: To explore how RUNX1 mutations predispose to leukemia, we generated induced pluripotent stem cells (iPSCs) from 2 pedigrees with germline RUNX1 mutations. The first, carrying a missense R174Q mutation, which acts as a dominant-negative mutant, is associated with thrombocytopenia and leukemia, and the second, carrying a monoallelic gene deletion inducing a haploinsufficiency, presents only as thrombocytopenia. Hematopoietic differentiation of these iPSC clones demonstrated profound defects in erythropoiesis and megakaryopoiesis and deregulated expression of RUNX1 targets. iPSC clones from patients with the R174Q mutation specifically generated an increased amount of granulomonocytes, a phenotype reproduced by an 80% RUNX1 knockdown in the H9 human embryonic stem cell line, and a genomic instability. This phenotype, found only with a lower dosage of RUNX1, may account for development of leukemia in patients. Altogether, RUNX1 dosage could explain the differential phenotype according to RUNX1 mutations, with a haploinsufficiency leading to thrombocytopenia alone in a majority of cases whereas a more complete gene deletion predisposes to leukemia.

SUBMITTER: Antony-Debre I

PROVIDER: S-EPMC4347283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Genetic alterations in the RUNX1 gene are associated with benign and malignant blood disorders, particularly of megakaryocyte and myeloid lineages. The role of RUNX1 in acute lymphoblastic leukemia (ALL) is less clear, particularly how germline genetic variation influences the predisposition to this type of leukemia. Sequencing 4,836 children with B-ALL and 1,354 cases of T-ALL, we identified 31 and 18 germline RUNX1 variants, respectively. RUNX1 variants in B-ALL consistently showed minimal damaging effects. By contrast, 6 T-ALL-related variants result in drastic loss of RUNX1 activity as a transcription activator in vitro. Ectopic expression of dominant-negative RUNX1 variants in human CD34+ cells repressed differentiation into erythroid, megakaryocytes, and T cells, while promoting myeloid cell development. Chromatin immunoprecipitation sequencing of T-ALL models showed distinctive patterns of RUNX1 binding by variant proteins. Further whole genome sequencing identified JAK3 mutation as the most frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Co-introduction of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mice gave rise to T-ALL with early T-cell precursor phenotype. Taken together, these results indicated that RUNX1 is an important predisposition gene for T-ALL and pointed to novel biology of RUNX1-mediated leukemogenesis in the lymphoid lineages.

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Beyond Pathogenic <i>RUNX1</i> Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies.

Project description:Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.

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Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-31 | GSE178239 | GEO

Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice.

Project description:Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) is not well-understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase in the number of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the BM. Furthermore, the expression of CD48, another inflammation-response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild-type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.

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