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Lovisa, Federica (2013) Ultra-deep mutational analysis of NPM-ALK and possible implications on target therapy in anaplastic large cell lymphoma of childhood. [Tesi di dottorato]

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Abstract (inglese)

Anaplastic Large Cell Lymphoma (ALCL) represents a distinct subset of aggressive T-cell non-Hodgkin lymphoma (NHL) accounting for about 3% of adult NHL and 10 to 15% of childhood lymphomas. In the vast majority of the cases, ALCL is associated to chromosomal translocations, the most frequent being the t(2;5)(p23;q35), involving the Anaplastic Lymphoma Kinase (ALK) gene, which lead to aberrant NPM-ALK protein expression and kinase activity. It has been extensively demonstrated that aberrant
NPM-ALK expression contributes to the pathogenesis of ALK-positive ALCL, as it causes cell transformation through activation of several biological pathways related to cell proliferation, cell-cycle control and apoptosis. Although ALK-positive ALCL have a rather benign prognosis when treated with standard chemotherapy, the failure rate at two years is almost 30% for most of these regimens. Notably, most of relapses occur within the first year from the start of therapy, and long-term survival for relapsed disease is less than 50%. Aberrant ALK activity is one of the major oncogenic events not only in ALK-positive ALCL, but also in neuroblastoma, non-small cell lung cancer (NSCLC) and inflammatory myofibroblastic tumour (IMT) bearing ALK activating mutations/rearrangements, and the inhibition of ALK kinase activity was proven to substantially reduce cancer cell proliferation and invasiveness both in vitro and in vivo. Successful clinical experience with crizotinib further support the concept of ALK-specific inhibition as a valuable treatment strategy in ALK-positive ALCL, as well as in other
ALK-addicted tumours. However, similarly to other inhibitors selectively targeting oncogenic kinases, data on relapse to crizotinib due to newly acquired secondary mutations were reported. In this context, although a robust clinical response of ALCL patients to an ALK inhibitor is expected, some of those patients are also anticipated to develop resistance, making the knowledge of NPM-ALK kinase domain (KD) mutational status a valuable and mandatory information to the rational design of ALK-targeted therapies.
To detect somatic tumour mutations with potential utility for predicting treatment response in ALK-positive ALCL patients, we performed ultra-deep sequencing analysis on ALK exons 22-25, corresponding to the entire KD coding region, in 37 ALCL pediatric patients. Two low frequent point mutations were identified in two distinct cases, corresponding to the R1275Q and R1231Q amino acid changes. The R1275Q mutation has been already reported as one of the most frequent activating mutations in neuroblastoma, while the R1231Q amino acid substitution represents a novel ALK point mutation, which to our knowledge has never been reported neither in ALK receptor nor in other ALK-translocated kinases. The molecular implications of R1275Q and R1231Q point substitutions on NPM-ALK function and sensitivity to ALK-specific inhibition are still under our investigation. In addition to point mutation, oncokinase alternative spliced transcripts have been previously reported in patients with Bcr-Abl positive chronic myeloid leukemia and more recently ALK receptor isoforms were described in neuroblastoma. To our knowledge, however, NPM-ALK alternative splicing events have never been described. For the first time, we identified and characterized 9 NPM-ALK INDEL mutations, resulting from KD whole exons skipping or alternative canonical splicing sites recognition. To investigate the effect of INDEL mutations on the structure and activity of NPM-ALK, we performed molecular homology modelling and in vitro functional analysis. While all these mutants were shown to be kinase dead, we demonstrated that, when coespressed with wild-type NPM-ALK, these INDELs do interact with wild-type monomers and are likely to inhibit ALK kinase activity and increase sensitivity to treatment with crizotinib. This work demonstrates that NPM-ALK KD point mutations are extremely rare in newly diagnosed ALCL patients, but positive selection of mutated cells could not be excluded in case of an ALK-targeting therapy. Conversely, our results suggest that alternative splicing in NPM-ALK may represent a common event. A clear correlation between the presence of these variants and outcome could not be detected, possibly because of the restricted cohort of patients analyzed. However, we hypothesize that a significant impact of these mutations could be observed if an ALK-specific treatment is used. Patients bearing a consistent level of inactive NPM-ALK are therefore expected to respond differently to ALK kinase inhibitors; whether such a response will be increased or decreased, it remains to be elucidated.

Abstract (italiano)

Il linfoma anaplastico a grandi cellule (ALCL) è un sottotipo di linfoma non-Hodgkin (LNH) aggressivo prevalentemente a fenotipo T e rappresenta circa il 3% dei LNH dell’adulto e il 10-15% dei linfomi pediatrici. Nella maggioranza dei casi, l’ALCL è associato alla presenza di traslocazioni cromosomiche che coinvolgono il gene della chinasi ALK (Anaplastic Lymphoma Kinase), la più frequente delle quali è la t(2;5)(p23;q35), che determina l’espressione aberrante della chinasi di fusione NPM-ALK, costitutivamente attiva. È stato ampiamente dimostrato che l’espressione aberrante di NPM-ALK contribuisce alla patogenesi dell’ALCL, esercitando la sua attività trasformante mediante l’attivazione di numerosi vie di trasduzione del segnale connesse alla proliferazione, al controllo del ciclo cellulare e all’apoptosi. Sebbene gli ALCL che esprimono ALK siano caratterizzati da una prognosi piuttosto favorevole, quando trattati secondo i protocolli terapeutici standard, la percentuale di fallimento di questo tipo di terapie si attesta comunque intorno al 30%. Inoltre, la maggior parte delle recidive si verifica entro un anno dall’inizio del trattamento e la sopravvivenza dei pazienti recidivati non raggiunge il 50%. La deregolazione di ALK rappresenta uno degli eventi oncogenici più importanti non soltanto nel ALCL, ma anche nel neuroblastoma, nel tumore a piccole cellule del polmone (NSCLC) e nel tumore miofibroblastico infiammatorio (IMT) che presentano mutazioni o riarrangiamenti del gene ALK. Studi in vitro ed in vivo hanno dimostrato che l’inibizione dell’attività chinasica di ALK riduce in modo significativo la proliferazione e l’invasività delle cellule tumorali. Inoltre, l’inibitore di ALK crizotinib si è dimostrato molto efficace per il trattamento di pazienti affetti da NSCLC, ad ulteriore dimostrazione che l’inibizione dell’attività catalitica di questa proteina potrebbe rappresentare una strategia terapeutica promettente anche nell’ALCL ALK-positivo, così come in altri tumori associati ad espressione aberrante di ALK. Tuttavia, analogamente a quanto è stato osservato con altri inibitori di tirosin chinasi oncogene, alcuni pazienti in corso di trattamento con crizotinib sono recidivati in seguito all’insorgenza di mutazioni a carico della chinasi bersaglio. In questo contesto, sebbene una terapia di questo tipo possa essere estremamente efficace per il trattamento dell’ALCL, è necessario tenere presente che alcuni pazienti potrebbero sviluppare resistenza. Risulta quindi di fondamentale importanza conoscere lo stato mutazionale del dominio chinasico di NPM-ALK per poter pianificare una strategia terapeutica il più possibile efficace. Allo scopo di identificare mutazioni somatiche di NPM-ALK potenzialmente associate alla risposta al trattamento in pazienti con ALCL ALK-positivo, abbiamo sequenziato gli esoni 22-25 di NPM-ALK, corrispondenti all’intero dominio chinasico, in 37 pazienti con ALCL pediatrico, utilizzando un approccio di Next-Generation sequencing. In due pazienti distinti abbiamo identificato due mutazioni puntiformi a bassa frequenza, corrispondenti alle sostituzioni aminoacidiche R1275Q e R1231Q. La prima mutazione era già stata riportata nel neuroblastoma tra le più frequenti mutazioni attivanti, mentre la mutazione R1231Q non era nota né per ALK recettore, né in tumori in cui ALK è traslocato. Le implicazioni molecolari di queste mutazioni sull’attività di NPM-ALK e sulla sua sensibilità al trattamento con inibitori specifici sono oggetto di ulteriori studi in corso. Oltre alle mutazioni puntiformi, la presenza di trascritti derivanti da fenomeni di splicing alternativo è un fenomeno già noto per altre protein chinasi di fusione, come Bcr-Abl nella leucemia mieloide cronica, ma anche in ALK in pazienti affetti da neuroblastoma. Sulla base delle nostre conoscenze, tali fenomeni, tuttavia, non sono mai stati descritti per NPM-ALK. Per la prima volta, abbiamo identificato e caratterizzato 9 mutazioni INDEL di NPM-ALK, associate alla perdita di interi esoni o al riconoscimento di siti di splicing canonici alternativi. Allo scopo di comprendere quali potessero essere gli effetti di queste mutazioni sull’attività di NPM-ALK, abbiamo condotto delle analisi di molecular homology modelling e studi funzionali in vitro. Sebbene tutti questi mutanti siano risultati inattivi, abbiamo dimostrato che se vengono coespressi assieme alla loro controparte funzionale sono in grado di formare dei complessi con essa, riducendone l’attività catalitica e aumentando la sensibilità della chinasi al trattamento con crizotinib.
Questo lavoro di tesi dimostra che mutazioni puntiformi del dominio chinasico di
NPM-ALK sono piuttosto rare nei pazienti con ALCL prima dell’inizio della terapia, anche se una selezione positiva delle cellule con la mutazione potrebbe verificarsi nel caso in cui venisse utilizzato un trattamento a base di inibitori specifici di ALK. Al contrario, abbiamo dimostrato che gli eventi di splicing alternativo di NPM-ALK sono maggiormente frequenti, anche se non è stato possibile dimostrare una correlazione tra la presenza di queste varianti e il decorso della malattia, probabilmente a causa della bassa numerosità della nostra casistica. Tuttavia, riteniamo che queste mutazioni potrebbero avere un impatto significativo nel caso in cui i pazienti venissero trattati con inibitori specifici di ALK. In particolare, pazienti che esprimono livelli rilevanti di isoforme inattive di NPM-ALK potrebbero rispondere diversamente al trattamento. Resta da stabilire se questa differenza possa tradursi in una maggiore o minore efficacia di una terapia anti-ALK in questi pazienti.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rosolen, Angelo
Correlatore:Bonvini, Paolo
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > EMATOONCOLOGIA, IMMUNOLOGIA E GENETICA
Data di deposito della tesi:28 Gennaio 2013
Anno di Pubblicazione:28 Gennaio 2013
Parole chiave (italiano / inglese):NPM-ALK, ALCL, crizotinib, target therapy, kinase inhibitors, mutation, next-generation sequencing
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:5578
Depositato il:14 Ott 2013 10:09
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