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Methotrexate (MTX) may be a feasible treatment option for myeloproliferative neoplasms (MPNs), according to preclinical research published in Haematologica.
Researchers tested low-dose MTX in mouse models that mimic human MPNs—essential thrombocythemia (ET) and polycythemia vera (PV).
The team found that MTX inhibited the JAK/STAT pathway, normalized some blood counts, and reduced splenomegaly in these mice.
“We have now shown pretty conclusively that we can use this approach to treat mouse models of human MPNs, results which provide a much more tangible prospect of success in humans,” said study author Martin Zeidler, PhD, of the University of Sheffield in Sheffield, UK.
Dr Zeidler and his colleagues tested MTX in transgenic mice whose endogenous JAK2 locus had been replaced by the human JAK2 V617F allele. These mice develop ET-like disease when heterozygous and PV-like disease when homozygous.
The researchers first treated wild-type mice and hJAK2 V617F age-matched littermates with either MTX or vehicle control for 28 days. The results indicated that low-dose MTX inhibits the JAK/STAT pathway.
The team then compared MTX and ruxolitinib in hJAK2 V617F-expressing mice.
MTX reduced hemoglobin levels, red blood cell counts, and hematocrit levels in heterozygous and homozygous hJAK2 V617F mice.
MTX also normalized white cell counts in heterozygous and homozygous mice, but platelet numbers and mean corpuscular volume were not significantly affected by treatment.
The researchers said MTX was as effective as ruxolitinib in these mice, but MTX treatment doesn’t result in general myelosuppression.
When the team analyzed bone marrow in the MTX-treated hJAK2 V617F mice, they found no reduction in cellularity or differentiation in any of the 3 hematopoietic lineages.
The researchers noted that homozygous mice have erythrocytic and megakaryocytic hyperplasia and polylobated nuclei in a proportion of megakaryocytes, and these phenotypes are subjectively reduced in MTX-treated mice. This suggests a disease-specific effect of MTX, rather than non-specific myelosuppression.
Both MTX and ruxolitinib reduced splenomegaly in hJAK2 V617F mice.
However, the researchers said they observed “modest increases” in reticulocyte numbers and spleen size in wild-type mice treated with MTX. These mice also had “slight increases” in pSTAT5 and PIM1 mRNA levels, but these same changes did not occur in hJAK2 V617F mice.
The researchers therefore concluded that a “detailed molecular analysis” of the interactions between MTX and wild-type JAK2 is needed.
The team is also hoping to start testing MTX in a clinical trial early next year, as these preclinical results suggest the drug could be effective in patients with ET or PV. And this might make MTX a low-cost alternative to therapies currently used to treat MPNs.
“Repurposing MTX has the potential to provide a new, molecularly targeted treatment for MPN patients within a budget accessible to healthcare systems throughout the world—a development that may ultimately provide substantial clinical and health economic benefits,” Dr Zeidler said. 
Methotrexate (MTX) may be a feasible treatment option for myeloproliferative neoplasms (MPNs), according to preclinical research published in Haematologica.
Researchers tested low-dose MTX in mouse models that mimic human MPNs—essential thrombocythemia (ET) and polycythemia vera (PV).
The team found that MTX inhibited the JAK/STAT pathway, normalized some blood counts, and reduced splenomegaly in these mice.
“We have now shown pretty conclusively that we can use this approach to treat mouse models of human MPNs, results which provide a much more tangible prospect of success in humans,” said study author Martin Zeidler, PhD, of the University of Sheffield in Sheffield, UK.
Dr Zeidler and his colleagues tested MTX in transgenic mice whose endogenous JAK2 locus had been replaced by the human JAK2 V617F allele. These mice develop ET-like disease when heterozygous and PV-like disease when homozygous.
The researchers first treated wild-type mice and hJAK2 V617F age-matched littermates with either MTX or vehicle control for 28 days. The results indicated that low-dose MTX inhibits the JAK/STAT pathway.
The team then compared MTX and ruxolitinib in hJAK2 V617F-expressing mice.
MTX reduced hemoglobin levels, red blood cell counts, and hematocrit levels in heterozygous and homozygous hJAK2 V617F mice.
MTX also normalized white cell counts in heterozygous and homozygous mice, but platelet numbers and mean corpuscular volume were not significantly affected by treatment.
The researchers said MTX was as effective as ruxolitinib in these mice, but MTX treatment doesn’t result in general myelosuppression.
When the team analyzed bone marrow in the MTX-treated hJAK2 V617F mice, they found no reduction in cellularity or differentiation in any of the 3 hematopoietic lineages.
The researchers noted that homozygous mice have erythrocytic and megakaryocytic hyperplasia and polylobated nuclei in a proportion of megakaryocytes, and these phenotypes are subjectively reduced in MTX-treated mice. This suggests a disease-specific effect of MTX, rather than non-specific myelosuppression.
Both MTX and ruxolitinib reduced splenomegaly in hJAK2 V617F mice.
However, the researchers said they observed “modest increases” in reticulocyte numbers and spleen size in wild-type mice treated with MTX. These mice also had “slight increases” in pSTAT5 and PIM1 mRNA levels, but these same changes did not occur in hJAK2 V617F mice.
The researchers therefore concluded that a “detailed molecular analysis” of the interactions between MTX and wild-type JAK2 is needed.
The team is also hoping to start testing MTX in a clinical trial early next year, as these preclinical results suggest the drug could be effective in patients with ET or PV. And this might make MTX a low-cost alternative to therapies currently used to treat MPNs.
“Repurposing MTX has the potential to provide a new, molecularly targeted treatment for MPN patients within a budget accessible to healthcare systems throughout the world—a development that may ultimately provide substantial clinical and health economic benefits,” Dr Zeidler said.
Methotrexate (MTX) may be a feasible treatment option for myeloproliferative neoplasms (MPNs), according to preclinical research published in Haematologica.
Researchers tested low-dose MTX in mouse models that mimic human MPNs—essential thrombocythemia (ET) and polycythemia vera (PV).
The team found that MTX inhibited the JAK/STAT pathway, normalized some blood counts, and reduced splenomegaly in these mice.
“We have now shown pretty conclusively that we can use this approach to treat mouse models of human MPNs, results which provide a much more tangible prospect of success in humans,” said study author Martin Zeidler, PhD, of the University of Sheffield in Sheffield, UK.
Dr Zeidler and his colleagues tested MTX in transgenic mice whose endogenous JAK2 locus had been replaced by the human JAK2 V617F allele. These mice develop ET-like disease when heterozygous and PV-like disease when homozygous.
The researchers first treated wild-type mice and hJAK2 V617F age-matched littermates with either MTX or vehicle control for 28 days. The results indicated that low-dose MTX inhibits the JAK/STAT pathway.
The team then compared MTX and ruxolitinib in hJAK2 V617F-expressing mice.
MTX reduced hemoglobin levels, red blood cell counts, and hematocrit levels in heterozygous and homozygous hJAK2 V617F mice.
MTX also normalized white cell counts in heterozygous and homozygous mice, but platelet numbers and mean corpuscular volume were not significantly affected by treatment.
The researchers said MTX was as effective as ruxolitinib in these mice, but MTX treatment doesn’t result in general myelosuppression.
When the team analyzed bone marrow in the MTX-treated hJAK2 V617F mice, they found no reduction in cellularity or differentiation in any of the 3 hematopoietic lineages.
The researchers noted that homozygous mice have erythrocytic and megakaryocytic hyperplasia and polylobated nuclei in a proportion of megakaryocytes, and these phenotypes are subjectively reduced in MTX-treated mice. This suggests a disease-specific effect of MTX, rather than non-specific myelosuppression.
Both MTX and ruxolitinib reduced splenomegaly in hJAK2 V617F mice.
However, the researchers said they observed “modest increases” in reticulocyte numbers and spleen size in wild-type mice treated with MTX. These mice also had “slight increases” in pSTAT5 and PIM1 mRNA levels, but these same changes did not occur in hJAK2 V617F mice.
The researchers therefore concluded that a “detailed molecular analysis” of the interactions between MTX and wild-type JAK2 is needed.
The team is also hoping to start testing MTX in a clinical trial early next year, as these preclinical results suggest the drug could be effective in patients with ET or PV. And this might make MTX a low-cost alternative to therapies currently used to treat MPNs.
“Repurposing MTX has the potential to provide a new, molecularly targeted treatment for MPN patients within a budget accessible to healthcare systems throughout the world—a development that may ultimately provide substantial clinical and health economic benefits,” Dr Zeidler said.