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LSK derived LSK- cells have a high apoptotic rate related to survival regulation of hematopoietic and leukemic stem cells.

Peng C, Chen Y, Shan Y, Zhang H, Guo Z, Li D, Li S - PLoS ONE (2012)

Bottom Line: Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells.In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population.These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
A balanced pool of hematopoietic stem cells (HSCs) in bone marrow is tightly regulated, and this regulation is disturbed in hematopoietic malignancies such as chronic myeloid leukemia (CML). The underlying mechanisms are largely unknown. Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells. Depletion of LSK cells by radiation or the cytotoxic chemical 5-fluorouracil results in an expansion of the LSK(-) population. In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population. The transition of LSK to LSK(-) cells is controlled by the Icsbp gene and its downstream gene Lyn, and regulation of this cellular transition is critical for the survival of normal LSK cells and LSCs. These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs.

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Irradiation and 5-FU treatment promote cellular transition of LSK to LSK− cells.(A) Lethal irradiation causes an increase in the percentage of apoptotic LSK− cells. Mice were treated by two split doses of 550-cGy gamma irradiation (separated by 3 hours), and the apoptotic cells (7AAD+Annexin V+) in the LSK− population were analyzed by FACS at different time points (n = 4). **: p<0.01. (B) Total number and percentages of LSK and LSK− cells in bone marrow of lethally irradiated WT mice were determined at different time points (n = 4). *: p<0.05; **: p<0.01. (C) Total number and percentages of LSK and LSK− in bone marrow of 5-FU treated WT mice at different time points. The mice were treated with 5-FU (200 mg/kg) by intravenous injection, and the percentages of LSK and LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01. (D) The apoptotic rate of LSK− cells in 5-FU treated mice. WT mice were treated with 5-FU, and apoptotic rate of LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01.
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pone-0038614-g002: Irradiation and 5-FU treatment promote cellular transition of LSK to LSK− cells.(A) Lethal irradiation causes an increase in the percentage of apoptotic LSK− cells. Mice were treated by two split doses of 550-cGy gamma irradiation (separated by 3 hours), and the apoptotic cells (7AAD+Annexin V+) in the LSK− population were analyzed by FACS at different time points (n = 4). **: p<0.01. (B) Total number and percentages of LSK and LSK− cells in bone marrow of lethally irradiated WT mice were determined at different time points (n = 4). *: p<0.05; **: p<0.01. (C) Total number and percentages of LSK and LSK− in bone marrow of 5-FU treated WT mice at different time points. The mice were treated with 5-FU (200 mg/kg) by intravenous injection, and the percentages of LSK and LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01. (D) The apoptotic rate of LSK− cells in 5-FU treated mice. WT mice were treated with 5-FU, and apoptotic rate of LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01.

Mentions: Because LSK− cells are derived from LSK cells [5] and incapable of giving rise to LSK cells (Fig. 1A), it is possible that LSK− cells regulates LSK cells through providing an apoptotic cellular pathway to regulate the pool size of the LSK population through controlling the degree of the transition of LSK cells to more apoptotic LSK− cells. To test this hypothesis, we examined whether induction of apoptosis of LSK cells is associated with an increase in the LSK− population in vivo. First, we lethally irradiated B6 mice, and found that the irradiation induced apoptosis of LSK cells in bone marrow (Fig. 2A), which accompanied with a decrease of LSK cells and an increase of LSK− cells (Fig. 2B). Second, we treated B6 mice with 5-FU, which has been shown to reduce LSK cells within initial two days of the treatment [14], and found that apoptosis of LSK cells also accompanied with a decrease of LSK cells and an increase of LSK− cells (Fig. 2C, D).


LSK derived LSK- cells have a high apoptotic rate related to survival regulation of hematopoietic and leukemic stem cells.

Peng C, Chen Y, Shan Y, Zhang H, Guo Z, Li D, Li S - PLoS ONE (2012)

Irradiation and 5-FU treatment promote cellular transition of LSK to LSK− cells.(A) Lethal irradiation causes an increase in the percentage of apoptotic LSK− cells. Mice were treated by two split doses of 550-cGy gamma irradiation (separated by 3 hours), and the apoptotic cells (7AAD+Annexin V+) in the LSK− population were analyzed by FACS at different time points (n = 4). **: p<0.01. (B) Total number and percentages of LSK and LSK− cells in bone marrow of lethally irradiated WT mice were determined at different time points (n = 4). *: p<0.05; **: p<0.01. (C) Total number and percentages of LSK and LSK− in bone marrow of 5-FU treated WT mice at different time points. The mice were treated with 5-FU (200 mg/kg) by intravenous injection, and the percentages of LSK and LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01. (D) The apoptotic rate of LSK− cells in 5-FU treated mice. WT mice were treated with 5-FU, and apoptotic rate of LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01.
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pone-0038614-g002: Irradiation and 5-FU treatment promote cellular transition of LSK to LSK− cells.(A) Lethal irradiation causes an increase in the percentage of apoptotic LSK− cells. Mice were treated by two split doses of 550-cGy gamma irradiation (separated by 3 hours), and the apoptotic cells (7AAD+Annexin V+) in the LSK− population were analyzed by FACS at different time points (n = 4). **: p<0.01. (B) Total number and percentages of LSK and LSK− cells in bone marrow of lethally irradiated WT mice were determined at different time points (n = 4). *: p<0.05; **: p<0.01. (C) Total number and percentages of LSK and LSK− in bone marrow of 5-FU treated WT mice at different time points. The mice were treated with 5-FU (200 mg/kg) by intravenous injection, and the percentages of LSK and LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01. (D) The apoptotic rate of LSK− cells in 5-FU treated mice. WT mice were treated with 5-FU, and apoptotic rate of LSK− cells were monitored at different time points (n = 4). *: p<0.05; **: p<0.01.
Mentions: Because LSK− cells are derived from LSK cells [5] and incapable of giving rise to LSK cells (Fig. 1A), it is possible that LSK− cells regulates LSK cells through providing an apoptotic cellular pathway to regulate the pool size of the LSK population through controlling the degree of the transition of LSK cells to more apoptotic LSK− cells. To test this hypothesis, we examined whether induction of apoptosis of LSK cells is associated with an increase in the LSK− population in vivo. First, we lethally irradiated B6 mice, and found that the irradiation induced apoptosis of LSK cells in bone marrow (Fig. 2A), which accompanied with a decrease of LSK cells and an increase of LSK− cells (Fig. 2B). Second, we treated B6 mice with 5-FU, which has been shown to reduce LSK cells within initial two days of the treatment [14], and found that apoptosis of LSK cells also accompanied with a decrease of LSK cells and an increase of LSK− cells (Fig. 2C, D).

Bottom Line: Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells.In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population.These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
A balanced pool of hematopoietic stem cells (HSCs) in bone marrow is tightly regulated, and this regulation is disturbed in hematopoietic malignancies such as chronic myeloid leukemia (CML). The underlying mechanisms are largely unknown. Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells. Depletion of LSK cells by radiation or the cytotoxic chemical 5-fluorouracil results in an expansion of the LSK(-) population. In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population. The transition of LSK to LSK(-) cells is controlled by the Icsbp gene and its downstream gene Lyn, and regulation of this cellular transition is critical for the survival of normal LSK cells and LSCs. These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs.

Show MeSH
Related in: MedlinePlus