Directly to content
  1. Publishing |
  2. Search |
  3. Browse |
  4. Recent items rss |
  5. Open Access |
  6. Jur. Issues |
  7. DeutschClear Cookie - decide language by browser settings

MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB

Cordas dos Santos, David M. ; Eilers, Juliane ; Vizcaino, Alfonso Sosa ; Orlova, Elena ; Zimmermann, Martin ; Stanulla, Martin ; Schrappe, Martin ; Börner, Kathleen ; Grimm, Dirk ; Muckenthaler, Martina U. ; Kulozik, Andreas E. ; Kunz, Joachim B.

In: BMC Cancer, 18 (2018), Nr. 663. pp. 1-12. ISSN 1471-2407

[img]
Preview
PDF, English
Download (2MB) | Lizenz: Creative Commons LizenzvertragMAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB by Cordas dos Santos, David M. ; Eilers, Juliane ; Vizcaino, Alfonso Sosa ; Orlova, Elena ; Zimmermann, Martin ; Stanulla, Martin ; Schrappe, Martin ; Börner, Kathleen ; Grimm, Dirk ; Muckenthaler, Martina U. ; Kulozik, Andreas E. ; Kunz, Joachim B. underlies the terms of Creative Commons Attribution 4.0

Citation of documents: Please do not cite the URL that is displayed in your browser location input, instead use the DOI, URN or the persistent URL below, as we can guarantee their long-time accessibility.

Abstract

Background: Deletions of 6q15–16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4.

Methods: MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR.

Results: MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α.

Conclusions: This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts.

Item Type: Article
Journal or Publication Title: BMC Cancer
Volume: 18
Number: 663
Publisher: BioMed Central ; Springer
Place of Publication: London ; Berlin ; Heidelberg
Date Deposited: 25 Jun 2018 13:11
Date: 2018
ISSN: 1471-2407
Page Range: pp. 1-12
Faculties / Institutes: Service facilities > German Cancer Research Center (DKFZ)
Medizinische Fakultät Heidelberg > Universitätskinderklinik
Medizinische Fakultät Heidelberg > Department for Infectiology
Subjects: 610 Medical sciences Medicine
About | FAQ | Contact | Imprint |
OA-LogoDINI certificate 2013Logo der Open-Archives-Initiative