scholarly journals Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

2008 ◽  
Vol 28 (20) ◽  
pp. 6234-6247 ◽  
Author(s):  
Brenda J. Chyla ◽  
Isabel Moreno-Miralles ◽  
Melissa A. Steapleton ◽  
Mary Ann Thompson ◽  
Srividya Bhaskara ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Cell Fate Decisions ◽  
Erythroid Progenitor Cells ◽  
Progenitor Cell Proliferation

ABSTRACT While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e.g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16 − / − defect.

scholarly journals Suppressive effects in vivo of purified recombinant human H-subunit (acidic) ferritin on murine myelopoiesis

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 74-79 ◽  
Author(s):  
HE Broxmeyer ◽  
DE Williams ◽  
K Geissler ◽  
G Hangoc ◽  
S Cooper ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Virus Complex ◽  
Progenitor Cell Proliferation ◽  
Dose Dependent

Purified recombinant human heavy-chain (acidic) ferritin (rHF) was assessed in vivo in mice for effects on the proliferation (percentage of cells in S-phase) and absolute numbers of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells in the femur and spleen and on the nucleated cells in the marrow, spleen, and blood. rHF significantly decreased cycling rates and absolute numbers of marrow and splenic hematopoietic progenitors and marrow and blood nucleated cellularity. These effects were apparent in BDF1, C3H/Hej and DBA/2 mice and were dose dependent, time related, and reversible. Suppressive effects were noted within three hours for progenitor cell cycling, within 24 hours for progenitor cell numbers, and within 48 hours for circulating neutrophils. Additionally, hematopoietic progenitor cells in DBA/2 mice infected with the polycythemia-inducing strain of the Friend virus complex (FVC-P) were insensitive to the in vivo administration of rHF. These studies demonstrate activity of rHF in vivo on myelopoiesis of normal but not FVC-P-infected mice. Since rHF suppresses hematopoietic progenitor cell proliferation from normal donors in vitro and from normal mice in vitro and in vivo but does not suppress progenitor cells from patients with leukemia in vitro or from mice with FVC-P-infection in vitro or in vivo, rHF may be useful as a candidate adjunct molecule for the protection of normal hematopoietic progenitor cells during chemotherapy.

scholarly journals Suppressive effects in vivo of purified recombinant human H-subunit (acidic) ferritin on murine myelopoiesis

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 74-79 ◽  
Author(s):  
HE Broxmeyer ◽  
DE Williams ◽  
K Geissler ◽  
G Hangoc ◽  
S Cooper ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Virus Complex ◽  
Progenitor Cell Proliferation ◽  
Dose Dependent

Abstract Purified recombinant human heavy-chain (acidic) ferritin (rHF) was assessed in vivo in mice for effects on the proliferation (percentage of cells in S-phase) and absolute numbers of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells in the femur and spleen and on the nucleated cells in the marrow, spleen, and blood. rHF significantly decreased cycling rates and absolute numbers of marrow and splenic hematopoietic progenitors and marrow and blood nucleated cellularity. These effects were apparent in BDF1, C3H/Hej and DBA/2 mice and were dose dependent, time related, and reversible. Suppressive effects were noted within three hours for progenitor cell cycling, within 24 hours for progenitor cell numbers, and within 48 hours for circulating neutrophils. Additionally, hematopoietic progenitor cells in DBA/2 mice infected with the polycythemia-inducing strain of the Friend virus complex (FVC-P) were insensitive to the in vivo administration of rHF. These studies demonstrate activity of rHF in vivo on myelopoiesis of normal but not FVC-P-infected mice. Since rHF suppresses hematopoietic progenitor cell proliferation from normal donors in vitro and from normal mice in vitro and in vivo but does not suppress progenitor cells from patients with leukemia in vitro or from mice with FVC-P-infection in vitro or in vivo, rHF may be useful as a candidate adjunct molecule for the protection of normal hematopoietic progenitor cells during chemotherapy.

MTG16, a Target of the T(16;21) in Acute Myeloid Leukemia, Is Required for Hematopoietic Stem and Progenitor Cell Functions

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 609-609
Author(s):  
Melissa Ann Steapleton ◽  
Isabel Moreno ◽  
Brenda Chyla ◽  
Scott Hiebert
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Rapid Expansion ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cell Functions ◽  
Erythroid Progenitor Cells

Abstract The t(8;21) and t(16;21) disrupt two closely related Myeloid Translocation Gene family members respectively, MTG8 and MTG16. Whereas the expression of MTG8 is highly regulated, MTG16 is more widely expressed and is the family member most highly expressed in hematopoietic stem cells. Therefore, to address the contribution of MTG16 to HSC functions and hematopoiesis, we created mice lacking this gene. We show that this transcriptional co-repressor is required for hematopoietic stem and progenitor cell functions such as cell fate decisions and early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells towards the granulocytic/macrophage lineage, while reducing the numbers of megakaryocyte-erythroid progenitor cells, which was shown using both flow cytometry and methylcellulose colony formation assays. In addition, inactivation of Mtg16 impaired the rapid expansion of long and short-term stem cells, multi-potent progenitor cells and megakaryocyte-erythroid progenitor cells that are required under hematopoietic stress/emergency. Due to this, the Mtg16-null mice could not respond to phenylhydrazine or 5-fluorouracil treatment and were completely defective in the colony forming unit-spleen (CFU-S) assays. Additionally, Mtg16-null bone marrow failed to repopulate the hematopoietic system when it was transplanted into an irradiated recipient mouse and also failed to compete with wild-type bone marrow in a competitive bone marrow transplant. This impairment appeared to be due to a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16(−/−) defect. Thus, like other key transcriptional co-repressors (e.g., the retinoblastoma protein, pRB, and the nuclear hormone co-repressor, N-CoR) Mtg16 is a key regulator of stem cell functions and lineage commitment in hematopoiesis.

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