Cytoskeleton Dynamics in Peripheral T Cell Lymphomas: An Intricate Network Sustaining Lymphomagenesis.

Defects in cytoskeleton functions support tumorigenesis fostering an aberrant proliferation and promoting inappropriate migratory and invasive features. The link between cytoskeleton and tumor features has been extensively investigated in solid tumors. However, the emerging genetic and molecular landscape of peripheral T cell lymphomas (PTCL) has unveiled several alterations targeting structure and function of the cytoskeleton, highlighting its role in cell shape changes and the aberrant cell division of malignant T cells. In this review, we summarize the most recent evidence about the role of cytoskeleton in PTCLs development and progression. We also discuss how aberrant signaling pathways, like JAK/STAT3, NPM-ALK, RhoGTPase, and Aurora Kinase, can contribute to lymphomagenesis by modifying the structure and the signaling properties of cytoskeleton

The DNA-helicase HELLS drives ALK - ALCL proliferation by the transcriptional control of a cytokinesis-related program.

Deregulation of chromatin modifiers, including DNA helicases, is emerging as one of the mechanisms underlying the transformation of anaplastic lymphoma kinase negative (ALK-) anaplastic large cell lymphoma (ALCL). We recently identified the DNA-helicase HELLS as central for proficient ALK-ALCL proliferation and progression. Here we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and transcriptional cooperators. We demonstrated that HELLS, together with the transcription factor YY1, contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow regulation. Binding target promoters, HELLS primes YY1 recruitment and transcriptional activation of cytoskeleton genes including the small GTPases RhoA and RhoU and their effector kinase Pak2. Single or multiple knockdowns of these genes reveal that RhoA and RhoU mediate HELLS effects on cell proliferation and cell division of ALK-ALCLs. Collectively, our work demonstrates the transcriptional role of HELLS in orchestrating a complex transcriptional program sustaining neoplastic features of ALK-ALCL

L'asse lncRNA BlackMamba-DNA elicasi HELLS guida la proliferazione delle cellule ALK-ALCL coordinando un complesso programma oncogenico trascrizionale

Nonostante siano stati fatti grandi progressi nella scoperta delle alterazioni genomiche, i meccanismi molecolari alla base della trasformazione del sottotipo di linfoma T anaplastico a grandi cellule ALK- sono stati chiariti solo in parte. Al fine di identificare nuovi driver molecolari in grado di promuovere la progressione dei linfomi anaplastici a grandi cellule (ALCL), è stato messo a punto un RNA-sequencing che ci ha permesso di scoprire 1208 nuovi long noncoding intergenici, includendo tra questi 18 long noncoding principalmente espressi negli ALCL. Per studi molecolari e funzionali la nostra attenzione si è concentrata su un nuovo long noncoding, BlackMamba, che è overespresso solo nei pazienti ALK-. Esperimenti di silenziamento genico hanno dimostrato come BlackMamba regoli la crescita, la formazione di colonie e la morfologia delle cellule ALK- . Dal punto di vista meccanicistico, BlackMamba interagisce fisicamente con l’elicasi HELLS controllando la sua espressione genica ed il suo reclutamento alle regioni promotoriali/regolatorie dei geni coinvolti nel controllo dell’organizzazione del citoscheletro e del processo di citocinesi. Siccome le DNA elicasi si comportano anche come fattori di rimodellamento della cromatina e stanno emergendo come nuove vulnerabilità di diversi setting tumorali, abbiamo valutato nel dettaglio la funzione di HELLS utilizzando una strategia che accoppia l’RNA sequencing all’utilizzo di tool di predizione bioinformatica per identificare i target e cooperatori trascrizionali di HELLS. Abbiamo dimostrato che HELLS insieme al fattore trascrizionale YY1, contribuisce ad un corretto processo di citocinesi attraverso la regolazione trascrizionale dei geni coinvolti nella regolazione della struttura e funzione del solco di scissione delle cellule in divisione. Legandosi ai promotori dei geni target, HELLS innesca il reclutamento di YY1 e l’ attivazione trascrizionale dei geni coinvolti nell’organizzazione citoscheletrica come le RhO GTPasi RhoA, RhoU e il loro effettore PAK2. Esperimenti di silenziamento singolo e combinato di questi geni, mettono in evidenza come RhoA e RhoU mediano gli effetti di HELLS sulla proliferazione e divisione delle cellule ALK-. Nel complesso, il nostro lavoro dimostra il ruolo chiave di HELLS nel dirigere un complesso programma trascrizionale che sostiene la proliferazione e la progressione delle cellule ALK-, contribuendo in questo modo alla patogenesi dei linfomi anaplastici ALK-.Although important steps forward have been made in the discovery of genomic alterations, the molecular mechanisms leading to the transformation of anaplastic lymphoma kinase negative (ALK−) anaplastic large cell lymphoma (ALCL) have been only in part elucidated. To identify new culprits which promote and drive ALCL, we performed a total transcriptome sequencing and discovered 1208 previously unknown intergenic long noncoding RNAs (lncRNAs), including 18 lncRNAs preferentially expressed in ALCL. We selected for molecular and functional studies an unknown lncRNA, BlackMamba, which is overexpressed only in ALK− ALCL patients. Knockdown experiments demonstrated that BlackMamba regulates cell growth and cell morphology of ALK−ALCL cells. Mechanistically, BlackMamba interacts with the DNA helicase HELLS controlling its expression and its recruitment to the promoter regions of cytoskeleton and cytokinesis-related genes, fostering their expression. Since the DNA-helicase HELLS acts also as chromatin modifiers and they are emerging as new vulnerabilities of different cancer settings, we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and transcriptional cooperators. We demonstrated that HELLS, together with the transcription factor YY1, contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow structure and regulation. Binding target promoters, HELLS primes YY1 recruitment and transcriptional activation of cytoskeleton genes including the small GTPases RhoA and RhoU and their effector kinase Pak2. Single or multiple knockdowns of these genes reveal that RhoA and RhoU mediate HELLS effects on cell proliferation and cell division of ALK−ALCLs. Collectively, our work demonstrates the key role of HELLS in orchestrating a complex transcriptional program sustaining ALK−ALCL proliferation and progression, contributing to ALK-ALCL pathogenesis

Long non-coding RNA mitophagy and ALK- anaplastic lymphoma associated transcript: a novel regulator of mitophagy in T cell lymphoma

: Long noncoding RNAs (lncRNAs) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of T-cell Lymphoma progression disease. Their role in the aggressive ALK- Anaplastic Large Cell Lymphoma (ALCL) subtype has been only in part elucidated. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCLs, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with an ALK- ALCL preferential expression, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondria quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining ALK- ALCL progression