RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes

Greif, Philipp A.; Konstandin, Nikola P.; Metzeler, Klaus H.; Herold, Tobias; Pasalic, Zlatana; Ksienzyk, Bianka; Dufour, Annika; Schneider, Friederike; Schneider, Stephanie; Kakadia, Purvi M.; Braess, Jan; Sauerland, Maria Cristina; Berdel, Wolfgang E.; Büchner, Thomas; Woermann, Bernhard J.; Hiddemann, Wolfgang; Spiekermann, Karsten; Bohlander, Stefan K.

doi:10.3324/haematol.2012.064667

Cited by 82 publications

(86 citation statements)

References 24 publications

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“…123,124 Greif and colleagues identified RUNX1 mutations in ;16% of patients with CN-AML. 128 The mutations represent a broad spectrum of missense, nonsense, and framehshift changes distributed throughout the protein, with a higher frequency in the RHD. 128 Overall, somatic mutations in RUNX1 are detected in approximately 3% of pediatric and 15% of adult de novo AML patients.…”

Section: Runx1 Somatic Mutations In Amlmentioning

confidence: 99%

Role of RUNX1 in hematological malignancies

Sood

Kamikubo

Liu

2017

Blood

367

319

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RUNX1 is a member of the core-binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. RUNX1 is one of the most frequently mutated genes in a variety of hematological malignancies. Germ line mutations in RUNX1 cause familial platelet disorder with associated myeloid malignancies. Somatic mutations and chromosomal rearrangements involving RUNX1 are frequently observed in myelodysplastic syndrome and leukemias of myeloid and lymphoid lineages, that is, acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia. More recent studies suggest that the wild-type RUNX1 is required for growth and survival of certain types of leukemia cells. The purpose of this review is to discuss the current status of our understanding about the role of RUNX1 in hematological malignancies.

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Section: Runx1 Somatic Mutations In Amlmentioning

confidence: 99%

Role of RUNX1 in hematological malignancies

Sood

Kamikubo

Liu

2017

Blood

367

319

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“…34 This 85 gene RUNX1 signature showed an overlap of 28 genes (33%) with differentially expressed genes in AML113 (supplemental Table 11). …”

Section: Distinct Gene Expression Pattern Of Aml113mentioning

confidence: 98%

Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis

Herold

Metzeler

Vosberg

et al. 2014

Blood

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Key Points• AML patients with isolated trisomy 13 have a very poor clinical outcome • Isolated trisomy 13 in AML is associated with a high frequency of mutations in SRSF2 (81%) and RUNX1 (75%)In acute myeloid leukemia (AML), isolated trisomy 13 (AML113) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML113 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML113 patients were inferior compared to other ELN Intermediate-II patients (n5855) (median RFS, 7.8 vs 14.1 months, P 5 .006; median OS 9.3 vs. 14.8 months, P 5 .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML113 to date, and reveals a striking clustering of lesions in a few genes, defining AML113 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers:

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“…This indicates that missense mutations in the helicase C domain may present as either germline or somatic, and care should be taken to ensure that both tumor and normal sources of DNA are used for screening to differentiate between these alternatives. Shared sites of germline and acquired mutation have precedence in other FHM, where several RUNX1 mutations (e.g., R204*, R204Q, R320*) are found both as germline mutations in families with FPD-MM and acquired in sporadic myeloid malignancy cohorts [25,26].…”

Section: Mutation Of Ddx41 In Familial Hematological Malignancies (Fhm)mentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes

Cited by 82 publications

References 24 publications

Role of RUNX1 in hematological malignancies

Role of RUNX1 in hematological malignancies

Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis

Myeloid neoplasms with germline DDX41 mutation

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