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Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.

Zhao W, Wei L, Tan D, Su G, Zheng Y, He C, Mao ZJ, Singleton TP, Yin B - PLoS ONE (2014)

Bottom Line: We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival.These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C.This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

View Article: PubMed Central - PubMed

Affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.

ABSTRACT
The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

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The effect of leukemic load on the survival of recipient mice.Fig. 3A) The survival of B6C3F1 mice receiving different dose of B117P cells and treated with either Ara-C or PBS. Each group included 12 mice. The mice were watched for 60 days. Fig. 3B) The white blood cell counts at different stages of transplanted leukemia in the mouse model. (a) before transplant, (b) after the first course of treatment. Fig. 3C) The abundance of B117 tag in the peripheral blood of recipient mice detected by q-PCR, taking β-actin as the reference, at different time points, (A) 2 days following the transplantation, (B) right before the treatment, (C) following the first course of treatment, (D) following the second course of treatment. *p<0.05, **p<0.01. The data were presented as mean +/− SD of triplicate.
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pone-0109198-g003: The effect of leukemic load on the survival of recipient mice.Fig. 3A) The survival of B6C3F1 mice receiving different dose of B117P cells and treated with either Ara-C or PBS. Each group included 12 mice. The mice were watched for 60 days. Fig. 3B) The white blood cell counts at different stages of transplanted leukemia in the mouse model. (a) before transplant, (b) after the first course of treatment. Fig. 3C) The abundance of B117 tag in the peripheral blood of recipient mice detected by q-PCR, taking β-actin as the reference, at different time points, (A) 2 days following the transplantation, (B) right before the treatment, (C) following the first course of treatment, (D) following the second course of treatment. *p<0.05, **p<0.01. The data were presented as mean +/− SD of triplicate.

Mentions: To examine whether AML load had an impact on the treatment outcome, three different numbers of B117P cells were transplanted into B6C3F1 mice, followed by treatment either with PBS as control groups, or with Ara-C according to the above described protocol. As can be seen in Fig. 3A, infusion of 1×104 of B117P cells followed by Ara-C treatment did not cause moribund animal within the period of observation, whereas only 3 (25%) mice died in the PBS control group, indicative of an insufficient induction of reproducible leukemia at this cell dose. When the number of cells increased up to 1×105 and 1×106, the survival of recipient mice became shorter. Consistent with our previous observations, Ara-C treatment delayed the onset of disease, relative to the control groups. Notably, Ara-C treated mice infused with 1×105 B117P cells survived significantly longer than those with 1×106 cells, indicating that a higher level of blast cell load was associated with poor survival of Ara-C treated mice.


Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.

Zhao W, Wei L, Tan D, Su G, Zheng Y, He C, Mao ZJ, Singleton TP, Yin B - PLoS ONE (2014)

The effect of leukemic load on the survival of recipient mice.Fig. 3A) The survival of B6C3F1 mice receiving different dose of B117P cells and treated with either Ara-C or PBS. Each group included 12 mice. The mice were watched for 60 days. Fig. 3B) The white blood cell counts at different stages of transplanted leukemia in the mouse model. (a) before transplant, (b) after the first course of treatment. Fig. 3C) The abundance of B117 tag in the peripheral blood of recipient mice detected by q-PCR, taking β-actin as the reference, at different time points, (A) 2 days following the transplantation, (B) right before the treatment, (C) following the first course of treatment, (D) following the second course of treatment. *p<0.05, **p<0.01. The data were presented as mean +/− SD of triplicate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196759&req=5

pone-0109198-g003: The effect of leukemic load on the survival of recipient mice.Fig. 3A) The survival of B6C3F1 mice receiving different dose of B117P cells and treated with either Ara-C or PBS. Each group included 12 mice. The mice were watched for 60 days. Fig. 3B) The white blood cell counts at different stages of transplanted leukemia in the mouse model. (a) before transplant, (b) after the first course of treatment. Fig. 3C) The abundance of B117 tag in the peripheral blood of recipient mice detected by q-PCR, taking β-actin as the reference, at different time points, (A) 2 days following the transplantation, (B) right before the treatment, (C) following the first course of treatment, (D) following the second course of treatment. *p<0.05, **p<0.01. The data were presented as mean +/− SD of triplicate.
Mentions: To examine whether AML load had an impact on the treatment outcome, three different numbers of B117P cells were transplanted into B6C3F1 mice, followed by treatment either with PBS as control groups, or with Ara-C according to the above described protocol. As can be seen in Fig. 3A, infusion of 1×104 of B117P cells followed by Ara-C treatment did not cause moribund animal within the period of observation, whereas only 3 (25%) mice died in the PBS control group, indicative of an insufficient induction of reproducible leukemia at this cell dose. When the number of cells increased up to 1×105 and 1×106, the survival of recipient mice became shorter. Consistent with our previous observations, Ara-C treatment delayed the onset of disease, relative to the control groups. Notably, Ara-C treated mice infused with 1×105 B117P cells survived significantly longer than those with 1×106 cells, indicating that a higher level of blast cell load was associated with poor survival of Ara-C treated mice.

Bottom Line: We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival.These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C.This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

View Article: PubMed Central - PubMed

Affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.

ABSTRACT
The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

Show MeSH
Related in: MedlinePlus