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New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.” 
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”