Transcription factor mutations as a cause of familial myeloid neoplasms

Churpek, Jane E.; Bresnick, Emery H.

doi:10.1172/jci120854

Cited by 46 publications

(45 citation statements)

References 199 publications

(234 reference statements)

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“…Moreover, the study of some pedigrees highlights the possible involvement of some genes in both tumorigenesis and leukemogenesis [44]. e de nition of intermediate phenotype typically de ned as "blend pedigree" leading to a high prevalence of both solid and hematological neoplasia is mandatory to clarify both the biological processes involved in the development of these di erent malignancies and for the establishment of an e cient treatment strategy and clinical survival.…”

Section: Discussionmentioning

confidence: 99%

ETV6: A Candidate Gene for Predisposition to “Blend Pedigrees”? A Case Report from the NEXT-Famly Clinical Trial

Bernardi

Farina

Zanaglio

et al. 2020

Case Reports in Hematology

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Background. The identification of germline mutations in familial leukemia predisposition genes by next generation sequencing is of pivotal importance. Lately, some “blend pedigrees” characterized by both solid and hematologic malignancies have been described. Some genes were recognized as related to this double predisposition, while the involvement of others is still a matter of debate. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. Case Presentation. We present our recent experience in the identification of an ETV6-mutated “blend pedigree,” suggesting the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia. The pedigree recognition started with a MDS case enrolled in the NEXT-Famly protocol. The patient presented 9 relatives affected by solid tumors and hematological malignancies. Following the clinical trial protocol, the patient underwent NGS analysis, which confirmed the presence of a mutation on the noncoding region of ETV6 both on tumor and on germline DNA. The mutation resulted was shared by the still alive affected relatives. Conclusion. This evidence supports the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia and the importance of the investigation of the noncoding regions of the genes as recently suggested by different expert groups.

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Section: Discussionmentioning

confidence: 99%

ETV6: A Candidate Gene for Predisposition to “Blend Pedigrees”? A Case Report from the NEXT-Famly Clinical Trial

Bernardi

Farina

Zanaglio

et al. 2020

Case Reports in Hematology

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“…The genetic profile of AML is notably heterogeneous, and only a few mutations (i.e., FLT3, NPM1, and DNMT3A) are present in more than a quarter of AML patients [15]. Transcription factors are a class of genes that are frequently altered in AML, such as PML, EVI1, GATA2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells [16]. Furthermore, a recent genomic analysis in over 1500 AML patients identified novel hotspot mutations in another critical transcription factor, such as MYC [17].…”

Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

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“…Similar to this case, most patients with FPD/AML will have a characteristic phenotype (Table 1) including mild to moderate thrombocytopenia with normal platelet size, platelet α or dense granule secretion defects and impaired platelet aggregation, particularly in response to collagen and epinephrine as well as a predisposition to hematologic malignancies. Although there is variability in disease onset in FPD/AML, 3 development of a hematologic malignancy is common with a lifetime risk of ~44%: AML and MDS are common, other malignancies occur less frequently (Table 1). [19][20][21][22][23] FPD/AML has a high but incomplete RUNX1 variant curation haematologica | 2020; 105(4) 877…”

Section: Example 1 Early Nonsense Variants (Parg204ter) (Path Withmentioning

confidence: 99%

“…2 To date, more than 65 genes have been associated with a predisposition to hematologic malignancies. 3 Recognizing the contribution of germline variation toward myeloid neoplasia, the 'WHO classification of Tumors of Hematopoietic and Lymphoid Tissues' incorporated the classification of myeloid neoplasia with germline predisposition in their 2016 revised edition. 4,5 In parallel, clinical laboratories are increasingly offering broad next-generation sequencing-based tests for patients with myeloid neoplasia for somatic testing, and will readily detect germline variants, if present in a patient.…”

Section: Introductionmentioning

confidence: 99%