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Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.
Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.
Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.
Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.
The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.
When the researchers knocked down Spi1, the myeloid skewing diminished.
“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”
The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.
These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.
To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.
After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.
The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.
Suppression of erythropoiesis
The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.
Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.
They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.
Suppression of lymphopoiesis
The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.
And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.
EVI1 nearly eliminated the peripheral B cells completely, they noted.
Expansion of myelopoiesis
The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.
But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.
The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.
All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.
The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.
They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.
When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.
Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.
The authors had no competing interests to disclose.
Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.
Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.
Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.
Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.
The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.
When the researchers knocked down Spi1, the myeloid skewing diminished.
“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”
The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.
These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.
To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.
After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.
The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.
Suppression of erythropoiesis
The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.
Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.
They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.
Suppression of lymphopoiesis
The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.
And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.
EVI1 nearly eliminated the peripheral B cells completely, they noted.
Expansion of myelopoiesis
The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.
But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.
The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.
All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.
The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.
They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.
When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.
Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.
The authors had no competing interests to disclose.
Preclinical research suggests the oncoprotein EVI1 can promote leukemogenesis by suppressing erythropoiesis and lymphopoiesis while shifting differentiation toward the expansion of myeloid cells.
Researchers developed a new mouse model that mimics chromosomal rearrangements at 3q26, which are associated with poor-prognosis acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.
Using the mouse model, the team demonstrated that EVI1 overexpression distorts hematopoiesis and markedly expands premalignant myelopoiesis that eventually results in leukemic transformation.
Archibald Perkins, MD, PhD, of the University of Rochester Medical Center in New York, and his colleagues published these findings in Nature Communications.
The team demonstrated that the “myeloid-skewed phenotype” is dependent upon EVI1-binding DNA. This upregulates Spi1 and encodes the master myeloid regulator PU.1.
When the researchers knocked down Spi1, the myeloid skewing diminished.
“It’s not so pie-in-the-sky anymore,” Dr. Perkins said, “to think we can interrupt the process within the genome that leads to leukemia.”
The researchers first created a mouse model of 3q26 AML with a tetracycline-inducible allele of EVI1 by inserting tetracycline operons within the first exon. This allowed the induction of all three isoforms of EVI1.
These mice were viable and fertile but had no phenotype, which indicated that the allele functioned normally unless induced.
To assess the effect of EVI1 overexpression, the researchers transplanted oncogene-expressing bone marrow mixed 1:1 with wild-type bone marrow into recipient mice.
After confirming successful engraftment, the researchers fed the mice doxycycline-treated food to induce EVI1. The team analyzed cells in the peripheral blood and bone marrow at 10 weeks post-induction.
The researchers observed a more than two-fold expansion of the EVI1-overexpressing compartment in the mouse model.
Suppression of erythropoiesis
The researchers analyzed erythroid lineage in the transplanted mice at 2, 6, and 10 weeks post-induction and found the EVI1-overexpressing cells did not contribute effectively to erythropoiesis.
Using flow cytometry, the researchers quantitated apoptosis and proliferation in erythroid progenitors. They observed a six-fold increase in apoptosis within the erythroblasts compared to wild-type cells.
They also observed a drop in the proliferation of proerythroblasts and erythroblasts compared to wild-type.
Suppression of lymphopoiesis
The researchers observed significantly lower numbers of EVI1-overexpressing B-lineage cells within the bone marrow at 6 and 10 weeks.
And at 10 weeks post-induction, the team observed a decrease in peripheral T cells from approximately 1,800 cells/µL to approximately 750 cells/µL.
EVI1 nearly eliminated the peripheral B cells completely, they noted.
Expansion of myelopoiesis
The team reported that, at 2 weeks post-induction, the EVI1-overexpressing bone marrow and control bone marrow showed the same number of myeloid cells.
But at 6 and 10 weeks post-induction, the EVI1-overexpressing myeloid compartment expanded markedly.
The researchers aged a cohort of five mice transplanted with the 1:1 mix of wild-type and EVI1 bone marrow cells to determine if chronic overexpression of EVI1 results in leukemia.
All five mice died at 90 to 119 days of doxycycline treatment. Analysis revealed AML in all mice. Bone marrows were replete with blasts, and the peripheral blood revealed severe anemia.
The researchers then proceeded to establish the relationship between EVI1 and Spi1/PU.1 transcriptional regulation.
They documented binding of EVI1 to the regulatory element -14kbURE, which, together with EVI1., induced upregulation of PU.1.
When the team knocked down PU.1, myeloid skewing diminished. This, they say, indicates PU.1 is necessary for EVI1-induced myeloid expansion.
Funding for this research was provided by the National Institutes of Health, New York State Stem Cell Science, the Wilmot Cancer Institute, and the Clinical and Translational Science Institute at the University of Rochester.
The authors had no competing interests to disclose.