Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/6-19-2014/larryhbern/Gene Switch Takes Blood Cells to Leukemia and Back Again
Summary
Loss-of-function mutations in a gene called Pax5 have been known to drive normal blood cells to turn into leukemia cells. Such mutations are permanent, so it remained unclear whether an initial, temporary loss of function would instigate an irreversible cascade of events leading to an accumulation of undifferentiated lymphoblasts, or whether an ongoing loss of function would be needed to maintain the disease state.
With the publication of a new study, the question has become more than academic. The study, by researchers at Melbourne’s Walter and Eliza Hall Institute, has not only shown that switching off Pax5 causes cancer in a murine model of B-progenitor acute lymphoblastic leukemia (B-ALL), it has also demonstrated that switching on Pax5 essentially cures the disease.
The results of the study appeared June 15 in the journal Genes & Development, in an article entitled “Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.” The article described how the researchers used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL.
“In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation,” wrote the authors. “Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity.”
Institute researcher Grace Liu noted that Pax5, which is frequently “lost” in childhood B-ALL, is essential for normal development of B cells. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous,” she said. “We have shown that restoring Pax5 function, even in cells that have already become cancerous, removes this ‘block,’ and enables the cells to develop into normal white blood cells.”
Simply restoring Pax5 sufficed to normalize cancer cells. That is, re-engaging the stalled differentiation program in immature white blood cells restored normal development “despite the presence of additional oncogenic lesions.”
Institute researcher Ross Dickins, Ph.D., said that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia: “While B-ALL has a relatively good prognosis compared with other cancers, current treatments can last years and have major side effects. By understanding how specific genetic changes drive B-ALL, it may be possible to develop more specific treatments that act faster with fewer side effects.”
“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr. Dickins added. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”
Pax5 is just one of about 100 genes known to suppress human tumors. Now that Pax5 has been scrutinized with genetic switch technology, the researchers speculate that similar technology could be used to characterize other tumor suppressor genes.
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.
This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.