Why Do Some Forms of Leukemia Only Affect Children? / Perché alcune forme di leucemia colpiscono solo i bambini?
Why Do Some Forms of Leukemia Only Affect Children? / Perché alcune forme di leucemia colpiscono solo i bambini?
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
Each year, 2,500 pediatric cancers are diagnosed in France, with one third of cases concerning leukemia - commonly known as blood cancer. Over recent decades, research into pediatric cancer has intensified and treatments have improved, but the prognosis remains particularly unfavorable for these young patients.
Acute myeloid leukemia (AML) accounts for 15% of cases of leukemia diagnosed in children and adolescents. Overall survival at 5 years is around 60%, with relapse being the most common cause of mortality.
Abnormal protein fusion
There are several subtypes of AML. One of the most aggressive, which is linked to treatment resistance and a particularly unfavorable prognosis, is acute megakaryoblastic leukemia (AML-M7). In their new study published in Cancer Discovery, the team focused their efforts specifically on this type of acute myeloid leukemia."
The scientists obtained samples from young patients with AML-M7. In 2012, their analysis of these samples had already revealed AML-M7 to frequently present genetic alterations that lead to the expression of an abnormal protein resulting from the fusion of the two proteins normally independent in the cell. At that time, although this fusion - known as ETO2-GLIS2 - had been identified in 30% of AML-M7 cases, the researchers could not explain its mechanism of action.
They also wanted to understand why AML-M7 is diagnosed in children who are on average a lot younger (under 2 years of age) than those diagnosed with the other pediatric AML subtypes (on average towards the age of 6).
"One of the objectives of our new study was to look at the mechanism of action of the ETO2-GLIS2 fusion, and to better elucidate its consequences. We wanted to answer two major questions, with the first being why this disease is specific to children - since the fusion is not found in adults, and then what the potential therapeutic avenues could be", explains Thomas Mercher.
This involved the researchers analyzing the characteristics of human leukemia cells and developing a mouse model to study the consequences of the ETO2-GLIS2 fusion.
Towards new therapeutic avenues
In this model, the researchers showed that this fusion is sufficient in order to rapidly induce aggressive leukemia, if it is activated in fetal hematopoietic cells. However, there is little to link its activation in adult cells with the development of leukemia. Moreover, blocking the ETO2-GLIS2 fusion in the in vivo model brings tumor proliferation to a halt, with the abnormal blood cells once again able to differentiate into normal blood cells.
These findings suggest that some forms of leukemia develop specifically in children because the properties of the fetal cells differ from those of adult cells.
Findings which also make it possible to propose new target mechanisms in fetal cells and pediatric leukemia in order to improve treatments for these patients. "We now want to understand exactly how this fusion works. Targeting it in order to directly inhibit it with molecules that could be used in patients is not something we are able to do at present, so instead we will identify and try to target the surrounding proteins that are important for it to function", concludes Thomas Mercher.
Acute myeloid leukemia (AML) accounts for 15% of cases of leukemia diagnosed in children and adolescents. Overall survival at 5 years is around 60%, with relapse being the most common cause of mortality.
Abnormal protein fusion
There are several subtypes of AML. One of the most aggressive, which is linked to treatment resistance and a particularly unfavorable prognosis, is acute megakaryoblastic leukemia (AML-M7). In their new study published in Cancer Discovery, the team focused their efforts specifically on this type of acute myeloid leukemia."
The scientists obtained samples from young patients with AML-M7. In 2012, their analysis of these samples had already revealed AML-M7 to frequently present genetic alterations that lead to the expression of an abnormal protein resulting from the fusion of the two proteins normally independent in the cell. At that time, although this fusion - known as ETO2-GLIS2 - had been identified in 30% of AML-M7 cases, the researchers could not explain its mechanism of action.
They also wanted to understand why AML-M7 is diagnosed in children who are on average a lot younger (under 2 years of age) than those diagnosed with the other pediatric AML subtypes (on average towards the age of 6).
"One of the objectives of our new study was to look at the mechanism of action of the ETO2-GLIS2 fusion, and to better elucidate its consequences. We wanted to answer two major questions, with the first being why this disease is specific to children - since the fusion is not found in adults, and then what the potential therapeutic avenues could be", explains Thomas Mercher.
This involved the researchers analyzing the characteristics of human leukemia cells and developing a mouse model to study the consequences of the ETO2-GLIS2 fusion.
Towards new therapeutic avenues
In this model, the researchers showed that this fusion is sufficient in order to rapidly induce aggressive leukemia, if it is activated in fetal hematopoietic cells. However, there is little to link its activation in adult cells with the development of leukemia. Moreover, blocking the ETO2-GLIS2 fusion in the in vivo model brings tumor proliferation to a halt, with the abnormal blood cells once again able to differentiate into normal blood cells.
These findings suggest that some forms of leukemia develop specifically in children because the properties of the fetal cells differ from those of adult cells.
Findings which also make it possible to propose new target mechanisms in fetal cells and pediatric leukemia in order to improve treatments for these patients. "We now want to understand exactly how this fusion works. Targeting it in order to directly inhibit it with molecules that could be used in patients is not something we are able to do at present, so instead we will identify and try to target the surrounding proteins that are important for it to function", concludes Thomas Mercher.
ITALIANO
Ogni anno in Francia vengono diagnosticati 2.500 tumori pediatrici, con un terzo dei casi di leucemia, comunemente noti come tumori del sangue. Negli ultimi decenni, la ricerca sul cancro pediatrico si è intensificata e i trattamenti sono migliorati, ma la prognosi rimane particolarmente sfavorevole per questi giovani pazienti.
La leucemia mieloide acuta (LMA) rappresenta il 15% dei casi di leucemia diagnosticata in bambini e adolescenti. La sopravvivenza globale a 5 anni è del 60% circa, con la ricaduta la causa più comune di mortalità.
Fusione proteica anormale
Esistono diversi sottotipi di AML. Uno dei più aggressivi, che è legato alla resistenza al trattamento e ad una prognosi particolarmente sfavorevole, è la leucemia megacarioblastica acuta (AML-M7). Nel loro nuovo studio pubblicato su Cancer Discovery, il gruppo ha concentrato i propri sforzi specificamente su questo tipo di leucemia mieloide acuta ".
Gli scienziati hanno ottenuto campioni da giovani pazienti con AML-M7. Nel 2012, la loro analisi di questi campioni aveva già rivelato che AML-M7 presentava frequentemente alterazioni genetiche che portano all'espressione di una proteina anormale risultante dalla fusione delle due proteine normalmente indipendenti nella cellula. A quel tempo, sebbene questa fusione - nota come ETO2-GLIS2 - fosse stata identificata nel 30% dei casi di AML-M7, i ricercatori non sono stati in grado di spiegare il suo meccanismo d'azione.
Volevano anche capire perché AML-M7 è diagnosticato in bambini che sono in media molto più giovani (di età inferiore ai 2 anni) rispetto a quelli con diagnosi di altri sottotipi di AML pediatrici (in media verso i 6 anni).
"Uno degli obiettivi del nostro nuovo studio era di esaminare il meccanismo d'azione della fusione ETO2-GLIS2 e chiarire meglio le sue conseguenze. Volevamo rispondere a due domande principali, in primo luogo perché questa malattia è specifica per i bambini - poiché la fusione non si trova negli adulti, e quindi quali potrebbero essere le potenziali vie terapeutiche ", spiega Thomas Mercher.
Ciò ha coinvolto i ricercatori nell'analisi delle caratteristiche delle cellule di leucemia umana e nello sviluppo di un modello murino per studiare le conseguenze della fusione ETO2-GLIS2.
Verso nuove strade terapeutiche
In questo modello, i ricercatori hanno dimostrato che questa fusione è sufficiente per indurre rapidamente la leucemia aggressiva, se attivata nelle cellule ematopoietiche fetali. Tuttavia, c'è poco da collegare alla sua attivazione nelle cellule adulte con lo sviluppo della leucemia. Inoltre, il blocco della fusione ETO2-GLIS2 nel modello in vivo interrompe la proliferazione del tumore, con le cellule del sangue anomale ancora una volta in grado di differenziarsi in cellule del sangue normali.
Questi risultati suggeriscono che alcune forme di leucemia si sviluppano specificamente nei bambini perché le proprietà delle cellule fetali differiscono da quelle delle cellule adulte.
Risultati che consentono anche di proporre nuovi meccanismi target nelle cellule fetali e nella leucemia pediatrica al fine di migliorare i trattamenti per questi pazienti. "Ora vogliamo capire esattamente come funziona questa fusione. Mirarla al fine di inibirla direttamente con molecole che potrebbero essere utilizzate nei pazienti non è qualcosa che siamo in grado di fare al momento, quindi invece identificheremo e proveremo a prendere di mira l'ambiente circostante proteine importanti per il suo funzionamento ", conclude Thomas Mercher.
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