High Levels of Constitutive WAF1/Cip1 Protein are Associated with Chemoresistance in Acute Myelogenous Leukemia

Wei Zhang, Tohru Kobayashi, Steven M. Kornblau, Anne Gambel, David Claxton, Albert B. Deisseroth

Research output: Contribution to journalArticle

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Abstract

The WAFl/Cipl gene product is an important regulator at the G, checkpoint in the cell cycle. WAFl/Cipl expression can be activated through p53-dependent and p53-independent pathways. The WAFl/Cipl protein binds to cyclin- dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. In this preliminary study, we analyzed with Western blot assays the steady-state levels of the WAFl/Cipl protein in the leukemia cells of 100 untreated acute myelogenous leukemia (AML) patients. Normal bone marrow cells from six donors were used as a control. The results of these analyses showed that the levels of the WAFl/Cipl protein were very low in normal marrow cells and in the leukemia cells of 83 AML patients. High levels of WAFl/Cipl were detected in 17 patients; these patients with high WAFl/Cipl levels were significantly less likely to achieve complete remission (41% versus 69%, P = 0.03) and were four times as likely to be resistant to therapy (47% versus 12%, P = 0.003) as patients with very low levels of WAFl/Cipl. Median survival was 38 weeks for patients having very low expression levels versus 11 weeks for patients having high expression levels (P = 0.04). The WAFl/Cipl level was an independent predictor for response but not survival in a stepwise multivariate regression analysis. Southern blotting analyses did not detect deletion of the WAFl/Cipl gene in the 12 negative WAFl/Cipl AML samples tested. Also, the level of WAF1/Cipl protein expression was not correlated with overexpression of cyclin Dl, cyclin E, proliferating cell nuclear antigen, cyclin-dependent kinase 4, or p53 in the leukemia cells. However, the levels of cyclin Dl, cyclin E, and cyclin-dependent kinase 4 were elevated in most of the AML samples compared with that in normal marrow. We hypothesize that high-level constitutively expressed WAFl/Cipl in tumor cells may result in an indolent state that is refractory to chemotherapy drugs. We conclude that the WAFl/Cipl expression level may be an important prognostic factor for response to therapy and survival in AML patients.

Original languageEnglish (US)
Pages (from-to)1051-1057
Number of pages7
JournalClinical Cancer Research
Volume1
Issue number9
StatePublished - Sep 1 1995

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Acute Myeloid Leukemia
Proteins
Cyclin-Dependent Kinase 4
Cyclin E
Leukemia
Cyclins
Survival
Bone Marrow
Cyclin-Dependent Kinases
Proliferating Cell Nuclear Antigen
Southern Blotting
Cell Cycle Checkpoints
Bone Marrow Cells
Genes
Cell Cycle
Phosphotransferases
Multivariate Analysis
Western Blotting
Regression Analysis
Tissue Donors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Zhang, W., Kobayashi, T., Kornblau, S. M., Gambel, A., Claxton, D., & Deisseroth, A. B. (1995). High Levels of Constitutive WAF1/Cip1 Protein are Associated with Chemoresistance in Acute Myelogenous Leukemia. Clinical Cancer Research, 1(9), 1051-1057.
Zhang, Wei ; Kobayashi, Tohru ; Kornblau, Steven M. ; Gambel, Anne ; Claxton, David ; Deisseroth, Albert B. / High Levels of Constitutive WAF1/Cip1 Protein are Associated with Chemoresistance in Acute Myelogenous Leukemia. In: Clinical Cancer Research. 1995 ; Vol. 1, No. 9. pp. 1051-1057.
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abstract = "The WAFl/Cipl gene product is an important regulator at the G, checkpoint in the cell cycle. WAFl/Cipl expression can be activated through p53-dependent and p53-independent pathways. The WAFl/Cipl protein binds to cyclin- dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. In this preliminary study, we analyzed with Western blot assays the steady-state levels of the WAFl/Cipl protein in the leukemia cells of 100 untreated acute myelogenous leukemia (AML) patients. Normal bone marrow cells from six donors were used as a control. The results of these analyses showed that the levels of the WAFl/Cipl protein were very low in normal marrow cells and in the leukemia cells of 83 AML patients. High levels of WAFl/Cipl were detected in 17 patients; these patients with high WAFl/Cipl levels were significantly less likely to achieve complete remission (41{\%} versus 69{\%}, P = 0.03) and were four times as likely to be resistant to therapy (47{\%} versus 12{\%}, P = 0.003) as patients with very low levels of WAFl/Cipl. Median survival was 38 weeks for patients having very low expression levels versus 11 weeks for patients having high expression levels (P = 0.04). The WAFl/Cipl level was an independent predictor for response but not survival in a stepwise multivariate regression analysis. Southern blotting analyses did not detect deletion of the WAFl/Cipl gene in the 12 negative WAFl/Cipl AML samples tested. Also, the level of WAF1/Cipl protein expression was not correlated with overexpression of cyclin Dl, cyclin E, proliferating cell nuclear antigen, cyclin-dependent kinase 4, or p53 in the leukemia cells. However, the levels of cyclin Dl, cyclin E, and cyclin-dependent kinase 4 were elevated in most of the AML samples compared with that in normal marrow. We hypothesize that high-level constitutively expressed WAFl/Cipl in tumor cells may result in an indolent state that is refractory to chemotherapy drugs. We conclude that the WAFl/Cipl expression level may be an important prognostic factor for response to therapy and survival in AML patients.",
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Zhang, W, Kobayashi, T, Kornblau, SM, Gambel, A, Claxton, D & Deisseroth, AB 1995, 'High Levels of Constitutive WAF1/Cip1 Protein are Associated with Chemoresistance in Acute Myelogenous Leukemia', Clinical Cancer Research, vol. 1, no. 9, pp. 1051-1057.

High Levels of Constitutive WAF1/Cip1 Protein are Associated with Chemoresistance in Acute Myelogenous Leukemia. / Zhang, Wei; Kobayashi, Tohru; Kornblau, Steven M.; Gambel, Anne; Claxton, David; Deisseroth, Albert B.

In: Clinical Cancer Research, Vol. 1, No. 9, 01.09.1995, p. 1051-1057.

Research output: Contribution to journalArticle

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AU - Zhang, Wei

AU - Kobayashi, Tohru

AU - Kornblau, Steven M.

AU - Gambel, Anne

AU - Claxton, David

AU - Deisseroth, Albert B.

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AB - The WAFl/Cipl gene product is an important regulator at the G, checkpoint in the cell cycle. WAFl/Cipl expression can be activated through p53-dependent and p53-independent pathways. The WAFl/Cipl protein binds to cyclin- dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. In this preliminary study, we analyzed with Western blot assays the steady-state levels of the WAFl/Cipl protein in the leukemia cells of 100 untreated acute myelogenous leukemia (AML) patients. Normal bone marrow cells from six donors were used as a control. The results of these analyses showed that the levels of the WAFl/Cipl protein were very low in normal marrow cells and in the leukemia cells of 83 AML patients. High levels of WAFl/Cipl were detected in 17 patients; these patients with high WAFl/Cipl levels were significantly less likely to achieve complete remission (41% versus 69%, P = 0.03) and were four times as likely to be resistant to therapy (47% versus 12%, P = 0.003) as patients with very low levels of WAFl/Cipl. Median survival was 38 weeks for patients having very low expression levels versus 11 weeks for patients having high expression levels (P = 0.04). The WAFl/Cipl level was an independent predictor for response but not survival in a stepwise multivariate regression analysis. Southern blotting analyses did not detect deletion of the WAFl/Cipl gene in the 12 negative WAFl/Cipl AML samples tested. Also, the level of WAF1/Cipl protein expression was not correlated with overexpression of cyclin Dl, cyclin E, proliferating cell nuclear antigen, cyclin-dependent kinase 4, or p53 in the leukemia cells. However, the levels of cyclin Dl, cyclin E, and cyclin-dependent kinase 4 were elevated in most of the AML samples compared with that in normal marrow. We hypothesize that high-level constitutively expressed WAFl/Cipl in tumor cells may result in an indolent state that is refractory to chemotherapy drugs. We conclude that the WAFl/Cipl expression level may be an important prognostic factor for response to therapy and survival in AML patients.

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