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Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).
Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.
“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.
“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”
Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.
The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.
To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.
The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.
In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.
Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.
Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.
TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.
The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers. 
Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).
Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.
“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.
“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”
Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.
The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.
To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.
The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.
In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.
Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.
Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.
TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.
The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers.
Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).
Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.
“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.
“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”
Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.
The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.
To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.
The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.
In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.
Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.
Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.
TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.
The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers.