Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are freque... more Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are frequent even after aggressive multiagent chemotherapy and allogeneic stem cell transplantation. AML is a biologically heterogeneous disease, characterized by frequent cytogenetic abnormalities and an increasing spectrum of genetic mutations and molecular aberrations. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation. These cells may persist after treatment and are probably responsible for disease relapse. This review will describe bench and translational research in LSCs and discuss how the data should be used to change the direction of developmental therapeutics and clinical trials in AML.
Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unf... more Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD...
Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been... more Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
We have previously shown that the plant-derived compound parthenolide (PTL) can impair the surviv... more We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.
Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant st... more Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leuke- mic stem cells (LSCs), have been docu- mented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found
There is now abundant evidence that stem-cell properties are highly relevant to the biology of se... more There is now abundant evidence that stem-cell properties are highly relevant to the biology of several human cancers. However, many key questions remain. At the most fundamental level, we must determine to what extent stem-cell biology is relevant to all the major forms of human cancer. For this reason, it is premature to overstate the general role of stem cells in cancer. Nonetheless, the eradication of cancer stem cells will be necessary to improve the outcome of treatment for at least some cancers. An interesting question is whether different types of cancer stem cells have the same Achilles' heel; it should be possible to determine whether the same tumor-specific mechanisms of growth and survival are active across multiple cancer types. Because certain features of normal stem cells are conserved in different tissues,81 determining whether there is similar conservation among cancer stem cells will be useful in the design of new therapies. Another important issue to investigat...
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias ... more Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.
Recent studies suggest that the population of malignant cells found in human acute myelogenous le... more Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38- or CD34+/HLA-DR-. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Ralpha or CD123) was strongly expressed in CD34+/CD38- cells (98 +/- 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38- cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Ralpha positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD1...
Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are freque... more Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are frequent even after aggressive multiagent chemotherapy and allogeneic stem cell transplantation. AML is a biologically heterogeneous disease, characterized by frequent cytogenetic abnormalities and an increasing spectrum of genetic mutations and molecular aberrations. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation. These cells may persist after treatment and are probably responsible for disease relapse. This review will describe bench and translational research in LSCs and discuss how the data should be used to change the direction of developmental therapeutics and clinical trials in AML.
Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unf... more Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD...
Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been... more Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
We have previously shown that the plant-derived compound parthenolide (PTL) can impair the surviv... more We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.
Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant st... more Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leuke- mic stem cells (LSCs), have been docu- mented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found
There is now abundant evidence that stem-cell properties are highly relevant to the biology of se... more There is now abundant evidence that stem-cell properties are highly relevant to the biology of several human cancers. However, many key questions remain. At the most fundamental level, we must determine to what extent stem-cell biology is relevant to all the major forms of human cancer. For this reason, it is premature to overstate the general role of stem cells in cancer. Nonetheless, the eradication of cancer stem cells will be necessary to improve the outcome of treatment for at least some cancers. An interesting question is whether different types of cancer stem cells have the same Achilles' heel; it should be possible to determine whether the same tumor-specific mechanisms of growth and survival are active across multiple cancer types. Because certain features of normal stem cells are conserved in different tissues,81 determining whether there is similar conservation among cancer stem cells will be useful in the design of new therapies. Another important issue to investigat...
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias ... more Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.
Recent studies suggest that the population of malignant cells found in human acute myelogenous le... more Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38- or CD34+/HLA-DR-. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Ralpha or CD123) was strongly expressed in CD34+/CD38- cells (98 +/- 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38- cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Ralpha positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD1...
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Papers by Monica Guzman