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Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.
Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.
“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.
“As a consequence, the mice lose their red blood cells and die.”
With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.
The team described their research in Blood.
The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.
“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”
The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.
Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.
Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.
This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.
To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.
Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.
“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.” 
Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.
Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.
“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.
“As a consequence, the mice lose their red blood cells and die.”
With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.
The team described their research in Blood.
The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.
“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”
The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.
Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.
Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.
This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.
To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.
Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.
“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”
Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.
Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.
“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.
“As a consequence, the mice lose their red blood cells and die.”
With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.
The team described their research in Blood.
The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.
“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”
The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.
Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.
Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.
This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.
To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.
Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.
“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”