MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells

Dina Stroopinsky; Jacalyn Rosenblatt; Keisuke Ito; Heidi Mills; Li Yin; Hasan Rajabi; Baldev Vasir; Turner Kufe; Katarina Luptakova; Jon Arnason; Caterina Nardella; James D. Levine; Robin M. Joyce; Ilene Galinsky; Yoram Reiter; Richard M. Stone; Pier Paolo Pandolfi; Donald Kufe; David Avigan

doi:10.1158/0008-5472.CAN-13-0677

MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells

Dina Stroopinsky, Jacalyn Rosenblatt, Keisuke Ito, Heidi Mills, Li Yin, Hasan Rajabi, Baldev Vasir, Turner Kufe, Katarina Luptakova, Jon Arnason, Caterina Nardella, James D. Levine, Robin M. Joyce, Ilene Galinsky, Yoram Reiter, Richard M. Stone, Pier Paolo Pandolfi, Donald Kufe, David Avigan

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34⁺/lineage^-/ CD38^- cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34⁺ populations as similar results were obtained with leukemic cells from patients with CD34^- disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1^high) led to development of leukemia in NOD-SCID IL2Rgamma^null (NSG) immunodeficient mice. In contrast, MUC1^low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.

Original language	English (US)
Pages (from-to)	5569-5579
Number of pages	11
Journal	Cancer research
Volume	73
Issue number	17
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-0677
State	Published - Sep 1 2013
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-13-0677

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Stroopinsky, D., Rosenblatt, J., Ito, K., Mills, H., Yin, L., Rajabi, H., Vasir, B., Kufe, T., Luptakova, K., Arnason, J., Nardella, C., Levine, J. D., Joyce, R. M., Galinsky, I., Reiter, Y., Stone, R. M., Pandolfi, P. P., Kufe, D., & Avigan, D. (2013). MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer research, 73(17), 5569-5579. https://doi.org/10.1158/0008-5472.CAN-13-0677

Stroopinsky, D, Rosenblatt, J, Ito, K, Mills, H, Yin, L, Rajabi, H, Vasir, B, Kufe, T, Luptakova, K, Arnason, J, Nardella, C, Levine, JD, Joyce, RM, Galinsky, I, Reiter, Y, Stone, RM, Pandolfi, PP, Kufe, D & Avigan, D 2013, 'MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells', Cancer research, vol. 73, no. 17, pp. 5569-5579. https://doi.org/10.1158/0008-5472.CAN-13-0677

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abstract = "Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34+/lineage-/ CD38- cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34- disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NOD-SCID IL2Rgammanull (NSG) immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.",

author = "Dina Stroopinsky and Jacalyn Rosenblatt and Keisuke Ito and Heidi Mills and Li Yin and Hasan Rajabi and Baldev Vasir and Turner Kufe and Katarina Luptakova and Jon Arnason and Caterina Nardella and Levine, {James D.} and Joyce, {Robin M.} and Ilene Galinsky and Yoram Reiter and Stone, {Richard M.} and Pandolfi, {Pier Paolo} and Donald Kufe and David Avigan",

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AU - Stroopinsky, Dina

AU - Rosenblatt, Jacalyn

AU - Ito, Keisuke

AU - Mills, Heidi

AU - Yin, Li

AU - Rajabi, Hasan

AU - Vasir, Baldev

AU - Kufe, Turner

AU - Luptakova, Katarina

AU - Arnason, Jon

AU - Nardella, Caterina

AU - Levine, James D.

AU - Joyce, Robin M.

AU - Galinsky, Ilene

AU - Reiter, Yoram

AU - Stone, Richard M.

AU - Pandolfi, Pier Paolo

AU - Kufe, Donald

AU - Avigan, David

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N2 - Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34+/lineage-/ CD38- cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34- disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NOD-SCID IL2Rgammanull (NSG) immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.

AB - Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34+/lineage-/ CD38- cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34- disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NOD-SCID IL2Rgammanull (NSG) immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.

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MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells

Abstract

ASJC Scopus subject areas

UN SDGs

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