Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis

Welsh, Seth J.; Churchman, Michelle L.; Togni, Marco; Mullighan, Charles G.; Hagman, James

doi:10.1038/leu.2017.166

Cited by 22 publications

(17 citation statements)

References 43 publications

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“…Evidence suggests that B-cell receptor (BCR) plays an important role not only in Ph + B-ALL but also in Ph − B-ALL, where several molecules, such as IL-7, modulate survival and cell death mechanisms [167]. Indeed, the precursor-B-cell receptor (pre-BCR) activation depends on different signals that are required to initiate several aberrant cellular processes in pre-B cells, such as abnormal proliferation.…”

Section: Targeted Therapy: Inhibition Of Mtor In Allmentioning

confidence: 99%

Targeting mTOR in Acute Lymphoblastic Leukemia

Simioni

Martelli

Zauli

et al. 2019

Cells

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Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.

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Section: Targeted Therapy: Inhibition Of Mtor In Allmentioning

confidence: 99%

Targeting mTOR in Acute Lymphoblastic Leukemia

Simioni

Martelli

Zauli

et al. 2019

Cells

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“…7 The EBF1 (EBF1) gene located at chromosome 5q33, is a nuclear transcription factor required for normal B-lineage speci cation, commitment, and development. 27 EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of STAT5 signaling, and gain of IL-7-independent cell proliferation. 27 Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the TM domain of PDGFRB.…”

Section: Discussionmentioning

confidence: 99%

Genetic Profile and Clinical Implications of PDGFRB Fusion in Adult B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Xu¹,

Bao²,

Liu³

et al. 2021

Preprint

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Background:To investigate the pathogenesis, genetic changes, treatment and prognosis of adult B-cell acute lymphoblastic leukemia (B-ALL) with platelet-derived growth factor receptor B (PDGFRB) fusion. Method：Clinical characteristics, treatment process and prognosis of 7 adult B-ALL patients with PDGFRB fusion were presented respectively, and the PDGFRB fusion was confirmed by fluorescence in situ hybridization, RNA sequencing and Polymerase Chain Reaction. Results: 7 adult B-ALL patients with PDGFRB fusion were presented respectively. There were 5 males and 2 females, with a median age of 21 (range, 17-39) years and a median white blood cell count of 7.85 (range, 2.30-111.25) ×10^9/L. The fusion partners were EBF1, SMIM3 and TERF2. Three of 7 cases received tyrosine kinase inhibitor (TKI) targeted therapy, and 4 of 7 cases received chimeric antigen receptor T -cell (CAR-T) therapy. A total of 6 (85.71%) cases underwent haploid hematopoietic stem cell transplantation (Haplo-HSCT). Overall response rate was 71.43% (4/7), and the common adverse reactions during induction were febrile neutropenia and nausea. Seventy-five percent (3/4) and 100% (6/6) of patients were minimal residual disease negative after CAR-T and Haplo-HSCT. To the last follow-up, 2 of 7 cases relapsed in 2 and 7 months after remission, respectively, and the estimated 36 months of Event-free survival and Overall survival was 75.0% and 66.7%.Conclusions: intensive therapy combined with CAR-T or TKI is needed to achieve deep remission, and sequential Haplo-HSCT may improve the prognosis of adult B-ALL with PDGFRB fusion.

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“…EBF1 is involved in the regulation of metabolic and inflammatory signaling pathways, and the loss of gene function results in impaired insulin and inflammatory signaling (Griffin et al, 2013). EBF1 plays a role in a variety of diseases including breast cancer (Fernandez-Jimenez et al, 2017; Garcia-Closas et al, 2013; Michailidou et al, 2013), coronary artery disease (Ehret et al, 2011; Li et al, 2017; Singh et al, 2015; Wain et al, 2011), Hodgkin lymphoma (Bohle et al, 2013), multiple sclerosis (Martinez et al, 2005; Sombekke et al, 2010), and leukemia (Heltemes-Harris et al, 2011; Mesuraca et al, 2015; Welsh et al, 2018). MEF2A and EBF1 are regulators for the DMAC2 gene, which was implicated in one cousin pair.…”

Section: Discussionmentioning

confidence: 99%

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

Miller

Ward

Staley

et al. 2020

Preprint

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Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional rare genetic variants associated with longevity using unique and powerful pedigree-based analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). Methods: From an existing biorepository of Utah pedigrees, four pedigrees were identified which exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on one set of elderly first- or second- cousins from each pedigree. Rare (<0.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation to other elderly relatives. Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values=0.001 and 0.0001, respectively). Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were originally observed. These candidate genes and variants warrant further investigation.

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Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis

Cited by 22 publications

References 43 publications

Targeting mTOR in Acute Lymphoblastic Leukemia

Targeting mTOR in Acute Lymphoblastic Leukemia

Genetic Profile and Clinical Implications of PDGFRB Fusion in Adult B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

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