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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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Long-term treatment of CML mice with imatinib fails to promote the transition of LSCs to BCR-ABL expressing LSK− cells.(A) Apoptotic rates between LSCs and BCR-ABL expressing LSK− cells in CML mice were compared. At day 14 after induction of CML, apoptotic rate in GFP+LSK− was slightly higher than that of LSCs. (B) The percentage of GFP+LSK− cells was increased after imatinib treatment for 12 days, beginning at day 8 after induction of CML (100 mg/kg). (C) The percentages of LSCs and GFP+LSK− cells in bone marrow of CML mice were compared after imatinib treatment for 55 days. *: p<0.05; **: p<0.01. (D) Icsbp expression was increased in bone marrow cells of mice treated with lethal irradiation. Bone marrow cells were collected from lethally irradiated mice at day 0, 2 and 4 after irradiation. Total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05. (E) Icsbp expression in bone marrow cells was determined in 5-FU treated mice. Bone marrow cells were collected from 5-FU treated mice at day 0, 2, 4 and 6 after the treatment, and total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05; **: p<0.01. (F) Proposed molecular model for the control of the transition of LSK/LSCs and LSK− cells. The balance between LSK and LSK− cells is controlled by the Icsbp/Lyn pathway in normal hematopoiesis and by Alox5 in BCR-ABL induced CML.
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pone-0038614-g006: Long-term treatment of CML mice with imatinib fails to promote the transition of LSCs to BCR-ABL expressing LSK− cells.(A) Apoptotic rates between LSCs and BCR-ABL expressing LSK− cells in CML mice were compared. At day 14 after induction of CML, apoptotic rate in GFP+LSK− was slightly higher than that of LSCs. (B) The percentage of GFP+LSK− cells was increased after imatinib treatment for 12 days, beginning at day 8 after induction of CML (100 mg/kg). (C) The percentages of LSCs and GFP+LSK− cells in bone marrow of CML mice were compared after imatinib treatment for 55 days. *: p<0.05; **: p<0.01. (D) Icsbp expression was increased in bone marrow cells of mice treated with lethal irradiation. Bone marrow cells were collected from lethally irradiated mice at day 0, 2 and 4 after irradiation. Total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05. (E) Icsbp expression in bone marrow cells was determined in 5-FU treated mice. Bone marrow cells were collected from 5-FU treated mice at day 0, 2, 4 and 6 after the treatment, and total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05; **: p<0.01. (F) Proposed molecular model for the control of the transition of LSK/LSCs and LSK− cells. The balance between LSK and LSK− cells is controlled by the Icsbp/Lyn pathway in normal hematopoiesis and by Alox5 in BCR-ABL induced CML.

Mentions: Because LSK− cells in bone marrow of WT and Icsbp−/− mice are more apoptotic than LSK cells (Fig. 1C and Fig. 5D), we thought that this cellular pathway controlled by Icsbp might also play a role in regulating LSCs in CML mice. To test this idea, we first examined whether BCR-ABL-expressing LSK− cells contain more apoptotic cells than LSCs in bone marrow of CML mice, and found that apoptotic cells in the GFP+LSK− cell population were two-fold higher than those in the GFP+LSK cell population (Fig. 6A). We wondered whether the effect of imatinib treatment is also associated with the LSK− cell population, and found that 20 days after CML induction, the percentage of LSK− population was about 3.93% in placebo treated CML mice and 8.62% in imatinib treated CML mice (Fig. 6B), suggesting that the therapeutic effect of imatinib is associated with increased cellular transition of LSK cells. Because the BCR-ABL kinase inhibitor imatinib has an initial therapeutic effect but does not eliminate LSCs in CML mice [7], [17], we reasoned that the failure of imatinib to cure CML mice should be associated with an inability of imatinib to cause an increase in the transition of LSCs to LSK− cells in CML mice treated for a long period of time. We observed that the percentage of LSK− cells in bone marrow of imatinib-treated CML mice increased transiently, but eventually decreased to a level similar to that in untreated CML mice (Fig. 6C). This result suggests that LSCs somehow find a way to overcome imatinib-mediated inhibition of the transition of LSCs to apoptotic LSK− cells.


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)

Long-term treatment of CML mice with imatinib fails to promote the transition of LSCs to BCR-ABL expressing LSK− cells.(A) Apoptotic rates between LSCs and BCR-ABL expressing LSK− cells in CML mice were compared. At day 14 after induction of CML, apoptotic rate in GFP+LSK− was slightly higher than that of LSCs. (B) The percentage of GFP+LSK− cells was increased after imatinib treatment for 12 days, beginning at day 8 after induction of CML (100 mg/kg). (C) The percentages of LSCs and GFP+LSK− cells in bone marrow of CML mice were compared after imatinib treatment for 55 days. *: p<0.05; **: p<0.01. (D) Icsbp expression was increased in bone marrow cells of mice treated with lethal irradiation. Bone marrow cells were collected from lethally irradiated mice at day 0, 2 and 4 after irradiation. Total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05. (E) Icsbp expression in bone marrow cells was determined in 5-FU treated mice. Bone marrow cells were collected from 5-FU treated mice at day 0, 2, 4 and 6 after the treatment, and total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05; **: p<0.01. (F) Proposed molecular model for the control of the transition of LSK/LSCs and LSK− cells. The balance between LSK and LSK− cells is controlled by the Icsbp/Lyn pathway in normal hematopoiesis and by Alox5 in BCR-ABL induced CML.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366951&req=5

pone-0038614-g006: Long-term treatment of CML mice with imatinib fails to promote the transition of LSCs to BCR-ABL expressing LSK− cells.(A) Apoptotic rates between LSCs and BCR-ABL expressing LSK− cells in CML mice were compared. At day 14 after induction of CML, apoptotic rate in GFP+LSK− was slightly higher than that of LSCs. (B) The percentage of GFP+LSK− cells was increased after imatinib treatment for 12 days, beginning at day 8 after induction of CML (100 mg/kg). (C) The percentages of LSCs and GFP+LSK− cells in bone marrow of CML mice were compared after imatinib treatment for 55 days. *: p<0.05; **: p<0.01. (D) Icsbp expression was increased in bone marrow cells of mice treated with lethal irradiation. Bone marrow cells were collected from lethally irradiated mice at day 0, 2 and 4 after irradiation. Total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05. (E) Icsbp expression in bone marrow cells was determined in 5-FU treated mice. Bone marrow cells were collected from 5-FU treated mice at day 0, 2, 4 and 6 after the treatment, and total RNA was extracted and Icsbp expression was determined by real-time PCR. *: p<0.05; **: p<0.01. (F) Proposed molecular model for the control of the transition of LSK/LSCs and LSK− cells. The balance between LSK and LSK− cells is controlled by the Icsbp/Lyn pathway in normal hematopoiesis and by Alox5 in BCR-ABL induced CML.
Mentions: Because LSK− cells in bone marrow of WT and Icsbp−/− mice are more apoptotic than LSK cells (Fig. 1C and Fig. 5D), we thought that this cellular pathway controlled by Icsbp might also play a role in regulating LSCs in CML mice. To test this idea, we first examined whether BCR-ABL-expressing LSK− cells contain more apoptotic cells than LSCs in bone marrow of CML mice, and found that apoptotic cells in the GFP+LSK− cell population were two-fold higher than those in the GFP+LSK cell population (Fig. 6A). We wondered whether the effect of imatinib treatment is also associated with the LSK− cell population, and found that 20 days after CML induction, the percentage of LSK− population was about 3.93% in placebo treated CML mice and 8.62% in imatinib treated CML mice (Fig. 6B), suggesting that the therapeutic effect of imatinib is associated with increased cellular transition of LSK cells. Because the BCR-ABL kinase inhibitor imatinib has an initial therapeutic effect but does not eliminate LSCs in CML mice [7], [17], we reasoned that the failure of imatinib to cure CML mice should be associated with an inability of imatinib to cause an increase in the transition of LSCs to LSK− cells in CML mice treated for a long period of time. We observed that the percentage of LSK− cells in bone marrow of imatinib-treated CML mice increased transiently, but eventually decreased to a level similar to that in untreated CML mice (Fig. 6C). This result suggests that LSCs somehow find a way to overcome imatinib-mediated inhibition of the transition of LSCs to apoptotic LSK− cells.

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