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Zorzi, Elisa (2009) Heat Shock Protein 70 nel linfoma anaplastico a grandi cellule: ruolo, espressione e correlazione con la tirosin chinasi NPM-ALK. [Tesi di dottorato]

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Abstract (inglese)

Anaplastic Large Cell Lymphoma (ALCL) belongs to the group of high grade non Hodgkin
Lymphomas, described as a T- or null-cells origin large-cell lymphoma. More than 90% of all
ALCL are characterized by the chromosomal translocation t(2;5)(p23;q35), which fuses the
ALK tyrosine kinase receptor with the nuclear NPM (nucleophosmin) genes. The resulting
constitutively activated kinase NPM-ALK, leads to activation of signaling pathways involved
in survival and cell proliferation through activation of PI3K/Akt and STAT3. More recently
NPM-ALK has been shown to regulate the activation of MEK, ERK1/2 and p38-MAPK, as
well. Previously we have demonstrated that treatment of NPM-ALK+ ALCL cells with
proteasome inhibitor Bortezomib (BZ) causes the induction of Hsp70, a heat shock protein
relevant for the maintenance of the cellular homeostasis through the conservation and correct
folding of newly synthesized and/or denatured proteins. This is also helpful for several tumor
models, in which drug-induced protein misfolding and degradation is preceded by cell cycle
arrest and apoptosis. In this study we evaluated the expression and functional role of Hsp70 in
ALCL cell lines and in lymph nodal biopsies, assessing its anti-apoptotic activity after drug
treatment (Bortezomib) or cellular stress (heat shock, HS). Our results demonstrate that
Hsp70 is over-expressed in NPM-ALK+ ALCL cell lines following activation of the hsp
transcription factor, HSF1, most likely through a positive feedback mechanism.
Furthermore, when assessing the anti-apoptotic activity of over-expressed Hsp70 after
Bortezomib (BZ) treatment in NPM-ALK+ cells, we demonstrated that Hsp70 prevents the
loss of mitochondrial membrane permeabilization by binding and sequestering pro-apoptotic
protein Bax into the cytoplasm, lowering drug sensitivity compared to NPM-ALK- cells.
Hsp70 expression analysis was extended to 23 biopsies of ALCL, 20 NPM-ALK+ and 3
NPM-ALK-. Tissue array analysis demonstrated that 20/20 NPM-ALK+ ALCL biopsies were
Hsp70 positive compared to 1/3 NPM-ALK- ALCL biopsies. Such a difference was also
statistically significant, whereas, due to the small number of cases, a statistical correlation
between Hsp70 expression and patient outcome could not be demonstrated. However it is
worth of noting that 4/6 (67%) patients with an Hsp70 expression value of 3 (in a range
between 0 and 3) relapsed or died compared to only 3/12 (25%) of the patients with a protein
expression value ranging between 0 and 2, regardless NPM-ALK status and activity.
Finally transcription of Hsp70 was evaluated by RQ-PCR in 4 healthy control lymph nodes
and 10 NPM-ALK+ ALCL lymph node biopsies, demonstrating that in NPM-ALK+ ALCL
lymph nodes over-expression of Hsp70 reflect increased gene promoter activity, respect to
4
healthy lymphonodes as verified also through a statistical analysis. To test if NPM-ALK
plays a role in Hsp70 induction via HSF1 activity, we treated ALCL cell lines with WHIP154,
an ATP-competitive small molecule inhibitor of ALK kinase, before exposing cells to
BZ o HS, and showed HSF1 retention in the cytoplasm and Hsp70 mRNA and protein
expression downregulation.
We further observed a marked down regulation of the MAPK p38, among the downstream
NPM-ALK effector proteins, along with the HSF1 inhibition described above. Notably,
inhibition of p38 reduced significantly Hsp70 expression in NPM-ALK+ ALCL cells,
supporting a role of the NPM-ALK/p38 axis in the regulation of the HSF1/hsp70 pathway in
these cells, but also encouraging future investigations. This kinase may have some effect on
HSF1, but this hypothesis warrants further investigation. Indeed citostatic concentrations of
Bortezomib and WHI-P154 given together induced cell death in NPM-ALK+ ALCL cell lines,
at least in part because of Hsp70 downregulation.

Abstract (italiano)

I linfomi anaplastici a grandi cellule (ALCL) pediatrici sono caratterizzati, per più dell’90%,
dalla presenza della caratteristica traslocazione cromosomica t(2;5) da cui origina il trascritto
codificante per NPM-ALK, chinasi oncogena essenziale per la trasformazione della cellula
linfoide normale e per la sopravvivenza della cellula neoplastica. Oltre al suo potenziale promitogenico
e antiapoptotico mediato dall’attivazione dei pathway di PI3K/Akt e STAT3, studi
recenti hanno dimostrato il ruolo di NPM-ALK nell’attivazione di MEK, ERK1/2 e p38-
MAPK. Tuttavia, nonostante le numerose conoscenze sull’attività trasformante di NPM-ALK
sia in vivo che in vitro, poco è noto sui meccanismi di chemioresistenza indotti dalla stessa
chinasi, anche se forte rimane l’interesse per lo sviluppo di strategie terapeutiche mirate per la
cura dell’ALCL.
In un nostro studio precedente abbiamo dimostrato che in linee cellulari di ALCL NPM-ALK
positive (NPM-ALK+) l’inibitore proteosomale Bortezomib (BZ) provoca l’induzione di
Hsp70, una heat shock protein normalmente coinvolta nella maturazione e nella preservazione
della conformazione della maggioranza delle proteine cellulari ma che induce anche fenomeni
di chemioresistenza in molti modelli sperimentali tumorali.
In questo studio abbiamo quindi valutato lo stato e la funzione di Hsp70 in linee cellulari e in
preparati istologici di pazienti pediatrici affetti da ALCL, e i possibili meccanismi di
resistenza al trattamento farmacologico (BZ) o allo stress cellulare (heat shock, HS) che
favorirebbero la sopravvivenza delle cellule NPM-ALK+. Abbiamo dimostrato che Hsp70
risulta espressa ad alti livelli nelle linee cellulari NPM-ALK+ grazie alla capacità di queste
cellule di attivare efficacemente il fattore di trascrizione delle hsp, HSF1. Dalle nostre analisi
è emerso inoltre che Hsp70 interagisce con HSF1 nella sua forma fosforilata e attiva, ma solo
nelle linee cellulari NPM-ALK+. Ciò lascia supporre che Hsp70 possa regolare positivamente
la trascrizione delle hsp mediante un meccanismo a feed-back.
Inoltre abbiamo dimostrato che, quando indotta dopo trattamento con BZ o shock termico, in
linee cellulari NPM-ALK+ Hsp70 previene la perdita dell’omeostasi mitocondriale e il rilascio
transmembrana di fattori apoptogenici, attraverso l’inibizione della proteina pro-apoptotica
mitocondriale Bax. Questo giustificherebbe la resistenza al trattamento farmacologico
evidenziata nelle linee cellulari NPM-ALK+ rispetto alla linea di ALCL che non esprime
NPM-ALK.
L’analisi dell’espressione di Hsp70 e’ stata quindi estesa a 23 preparati istologici di pazienti
pediatrici affetti da ALCL, 20 NPM-ALK+ e 3 NPM-ALK-. Mediante analisi
2
immunoistochimica, abbiamo verificato che la totalità delle biopsie NPM-ALK+ è risultata
positiva ad Hsp70, rispetto a solo uno su tre dei casi NPM-ALK-, confermando
statisticamente (p=0.019) una correlazione tra la presenza di NPM-ALK e Hsp70. Data la
limitata numerosità dei campioni non è stato possibile correlare in maniera statistica
l’espressione di Hsp70 con l’andamento della malattia, ma è da sottolineare come il 67% dei
casi (4/6) con elevata espressione di Hsp70 (valore attribuito pari a 3, in una scala di
espressione crescente da 0 a 3) siano recidivati o deceduti, contro solo il 25% (3/12) dei casi
con espressione della proteina assente o intermedia (compresa tra 0 e 2, nella stessa scala).
Abbiamo verificato poi, che l’espressione del trascritto Hsp70 in biopsie linfonodali di
bambini affetti da ALCL NPM-ALK+, è significativamente più elevata rispetto a quella
riscontrata nei linfonodi reattivi non patologici (p=0.049).
Per valutare il possibile ruolo di NPM-ALK nell’induzione di Hsp70, prima di esporre le
cellule di ALCL in studio a trattamento con BZ o a calore (HS), la sua attività chinasica è
stata inibita farmacologicamente (WHI-P154). I nostri studi dimostrano che nelle cellule
trattate con WHI-P154, sia singolarmente che in combinazione con BZ o HS, HSF1 rimane
localizzato nel citoplasma con conseguente calo del trascritto e dell’espressione di Hsp70.
Infine abbiamo dimostrato che la combinazione di dosi singolarmente non citotossiche, o al
più citostatiche di BZ e WHI-P154, inibisce la proliferazione cellulare e induce apoptosi nelle
linee cellulari che esprimono NPM-ALK, effetto al quale concorre l’inibizione della
trascrizione e dell’espressione di Hsp70, oltre ad altri numerosi fattori dipendenti dall’attività
della chinasi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rosolen, Angelo
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > EMATOONCOLOGIA E IMMUNOLOGIA
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):LINFOMA ANAPLASTICO A GRANDI CELLULE E HEAT SHOCK PROTEIN 70
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Pediatria
Codice ID:1642
Depositato il:29 Gen 2009
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