Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.
- Klíčová slova
- ALK positive ALCL, non‐Hodgkin's lymphoma, variant ALK,
- MeSH
- anaplastická lymfomová kináza * genetika analýza MeSH
- anaplastický velkobuněčný lymfom * genetika patologie MeSH
- dítě MeSH
- fúzní onkogenní proteiny genetika MeSH
- jaderné proteiny genetika metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- nukleofosmin * MeSH
- předškolní dítě MeSH
- prognóza MeSH
- tropomyosin MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ALK protein, human MeSH Prohlížeč
- anaplastická lymfomová kináza * MeSH
- fúzní onkogenní proteiny MeSH
- jaderné proteiny MeSH
- NPM1 protein, human MeSH Prohlížeč
- nukleofosmin * MeSH
- TPM3 protein, human MeSH Prohlížeč
- tropomyosin MeSH
The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.
- MeSH
- dítě MeSH
- lidé MeSH
- mladý dospělý MeSH
- nehodgkinský lymfom * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- MeSH
- B-buněčný lymfom * farmakoterapie MeSH
- cyklofosfamid terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- dítě MeSH
- doxorubicin terapeutické užití MeSH
- etoposid terapeutické užití MeSH
- lidé MeSH
- prednison terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- rituximab terapeutické užití MeSH
- vinkristin terapeutické užití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cyklofosfamid MeSH
- doxorubicin MeSH
- etoposid MeSH
- prednison MeSH
- rituximab MeSH
- vinkristin MeSH
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
- MeSH
- anaplastický velkobuněčný lymfom farmakoterapie genetika metabolismus patologie MeSH
- antigen Ki-1 genetika metabolismus MeSH
- imunokonjugáty farmakologie MeSH
- interleukin-15 farmakologie MeSH
- interleukin-2 farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- receptor interleukinu-2 - alfa-podjednotka genetika imunologie metabolismus MeSH
- receptory interleukinu-2 genetika imunologie metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- regulační oblasti nukleových kyselin MeSH
- represorové proteiny genetika metabolismus MeSH
- signální transdukce účinky léků MeSH
- transkripční faktory bZIP genetika metabolismus MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigen Ki-1 MeSH
- BATF3 protein, human MeSH Prohlížeč
- IL2RA protein, human MeSH Prohlížeč
- imunokonjugáty MeSH
- interleukin-15 MeSH
- interleukin-2 MeSH
- receptor interleukinu-2 - alfa-podjednotka MeSH
- receptory interleukinu-2 MeSH
- represorové proteiny MeSH
- transkripční faktory bZIP MeSH
Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
- MeSH
- aktivace transkripce MeSH
- difúzní velkobuněčný B-lymfom genetika patologie MeSH
- down regulace MeSH
- folikulární lymfom diagnóza genetika patologie MeSH
- forkhead transkripční faktory genetika MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- nádorová transformace buněk genetika patologie MeSH
- prognóza MeSH
- protoonkogenní proteiny c-myc genetika MeSH
- regulace genové exprese u nádorů * MeSH
- represorové proteiny genetika MeSH
- upregulace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- forkhead transkripční faktory MeSH
- FOXP1 protein, human MeSH Prohlížeč
- mikro RNA MeSH
- MIRN150 microRNA, human MeSH Prohlížeč
- protoonkogenní proteiny c-myc MeSH
- represorové proteiny MeSH
