Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

I retroelementi nella tumorigenesi: ruoli distinti di LINE-1 e HERV-K nella progressione tumorale

I retroelementi sono sequenze altamente ripetute disperse nel genoma, che codificano per una Trascrittasi Inversa (RT). Cellule e tessuti caratterizzati da una elevata capacità di proliferazione e un basso grado di differenziamento (come cellule tumorali o embrionali) esprimono alti livelli di RT che al contrario è scarsamente espressa in tessuti terminalmente differenziati. E’ noto da precedenti studi condotti nel nostro laboratorio che il trattamento di diverse linee cellulari tumorali con due inibitori non nucleosidici della RT, la nevirapina ed l’efavirenz, induce una riduzione della proliferazione e della tumorigenicità in in vitro e d in vivo e ne promuove il differenziamento (Mangiacasale et al., 2003; Sciamanna et al., 2005; per una review Sinibaldi- Vallebona et al., 2006). In questo lavoro ho dimostrato che gli inibitori della RT, inibiscono la proliferazione solo in delle cellule tumorali mentre non hanno alcun effetto significativo sulle cellule normali. Inoltre, utilizzando la tecnica dellRNA interference (RNAi) ho identificato due famiglie di retroelementi, LINE-1 e HERV-K, che hanno ruoli diversi nella tumorigenesi. Infettando cellule di melanoma A375 con vettori retrovirali adeguatamente ingegnerizzati allo scopo, ho prodotto due linee cellulari in cui l’espressione di questi due retroelementi sia stabilmente interferita. Le cellule interferite per il LINE-1 hanno una ridotta proliferazione, una morfologia alterata ed un’espressione alterata di alcuni geni che regolano la proliferazione e il differenziamento. Al contrario, le cellule A375 interferite per HERV-K non mostrano nessun cambiamento in vitro. A differenza di quanto osservato in vitro, entrambe le linee cellulari inoculate in topi nudi atimici hanno una ridotta tumorigenicità rispetto alle cellule della linea parentale. Infine, allo scopo di sviluppare una possibile terapia genica differenziativa dei tumori, ho sviluppato un sistema di vettori adenovirali in sostituzione di quelli retro virali; i primi infatti offrono una serie di vantaggi rispetto ai vettori retrovirali, primo fra tutti il fatto che queste sequenze rimangono in forma episomale consentendo quindi di ripetere l’infezione diverse volte allo scopo di migliorarne l’efficienzaRetroelements are sequences highly repeated present in all eucaryotic genomes and they encode for a RT that is expressed at high levels in cells and tissue types characterized by a high proliferative potential and a low degree of differentiation (e.g. embryonic tissues and tumor cells), whereas low RT levels are generally found in terminally differentiated, non pathological tissue. Previous studies have showed that inhibition of endogenous RT, using pharmacological inhibitors, (nevirapine and efavirenz) reduces proliferation and promotes differentiation of human tumorigenic cell lines and strongly antagonizes tumor progression in murine models (Mangiacasaele et al., 2003 Sciamanna et al., 2005; reviewed by Sinibaldi-Vallebona et al., 2006). In this work I have showed that the RT inhibitors, in contrast to what observed in tumorigenic cells, does not exert any effect on normal cells. In addition, I using a RNA interference approach (RNAi), I assessed the different roles of two retroelements LINE-1 and HERV-K in tumorigenesis and tumor progression. Using retroviral vectors, I produced two cell lines, derived from A375 melanoma cells, stably interfered for the expression of these elements. The cells in which LINE-1 expression was interfered exhibit a reduced proliferation and significant changes in morphology, suggestive of that a differentiation was activated. Moreover, these cells showed a reduced tumorigenecity when injected in nude mice. Instead, cells in which HERV-K expression was interfered the rate of proliferation and differentiation remain unchanged compared to the parental A375 cells. However, in vivo essays their tumorigenic potential was found to be reduced. Finally, aiming at the development of a novel gene therapy approach for cancer differentiation I developed an adenoviral delivery system which offers several advantages compared to retroviruses, most important the fact that adenodelivered sequences remain as non-integrated episomes and the infection can be repeated several times to improve the efficiency of infection

Genomic studies indicate a novel combination therapy for follicular lymphoma

Follicular lymphoma (FL) is an incurable form of B-cell lymphoma. Genomic alterations that inactivate RB signaling are surprisingly common in indolent FL. We show that FLs that are positive for phosphorylated RB respond to dual CDK4/BCL2 inhibition. Our results imply that RB phosphorylation identifies patients likely to benefit from such dual intervention

Functional genomics lead to new therapies in follicular lymphoma

Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody-based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody-mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies

Sestrin1, a tumor suppressor that can be rescued

SESTRIN1 is a tumor suppressor in follicular lymphoma that controls mTORC1 activity and it is inactivated by chromosomal deletions or epigenetically silenced by mutant EZH2Y641X. Pharmacological inhibition of EZH2 promotes SESTRIN1 re-expression and it restores its tumor suppressive activity, suggesting the possibility to epigenetically control mTORC1 activity

Progress against follicular lymphoma

To share the recent progress in research and new therapies against follicular lymphoma and highlight the exciting opportunities to improve the treatment of follicular lymphoma