Lenalidomide, a derivative of thalidomide, is a transformative therapy for a subset of patients with myelodysplastic syndrome, and has demonstrated promise in early clinical trials in acute myeloid leukemia (AML), but the mechanism of lenalidomide activity in myeloid malignancies is not known. We have identified and validated an E3 ubiquitin ligase, CRL4-CRBN, as a direct target of lenalidomide, consistent with previous reports that this complex is targeted by thalidomide. We hypothesize that the pleitropic effects of lenalidomide, including its therapeutic efficacy in myeloid malignancies, is due to altered ubiquitination of targets ofthe CRL4-CRBN ubiqutin ligase.
In Aim 1, we will use a recentiy developed proteomic approach to define the proteins that are differentially ubiquitinated in AML cells in response to lenalidomide, and we will validate that these proteins are direct targets of the CRL4-CRBN ubiquifin ligase using genetic tools and biochemical assays.
In Aim 2, we will use similar approaches to define the molecular basis of the immunomodulatory properties of lenalidomide that lead to alterations in the bone marrow microenvironment. These effects may be critical for the therapeutic efficacy of lenalidomide.
In Aim 3, we will investigate how altered ubiquitination of specific proteins may sensitize cells to additional therapies. Significant responses to lenalidomide as a single agent have been reported in AML, but only a subset of pafients respond, and complete remissions are of short duration. We will therefore seek to improve the therapeutic potential of lenalidomide by examing combinations with addifional therapies in collaboration with each of the other projects in this POl. In addition, we will examine ubiquitinated proteins and genetic abnormalities in patients treated with lenalidomide plus induction chemotherapy in a clinical trial proposed in Project 5. These studies will elucidate a novel mechanism for a cancer therapy, the direct targeting of a specific ubiquitin ligase with both cell autonomous and cell non-autonomous effects. In addition, we will identify novel combinations of lenalidomide with additional agents to develop more efficacious treatments for AML.

Public Health Relevance

Lenalidomide is an effective therapy for the treatment of specific hematologic malignancies, but its mechanism of action is unknown. We will examine the molecular basis for lenalidomide activity and identify novel approaches to the treatment of acute myeloid leukemia based on combinations of lenalidomide with additional therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA066996-19
Application #
9353316
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
19
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wan, Liling; Wen, Hong; Li, Yuanyuan et al. (2017) ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543:265-269
Weisberg, Ellen L; Puissant, Alexandre; Stone, Richard et al. (2017) Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase. Oncotarget 8:52026-52044
Pallis, Monica; Burrows, Francis; Ryan, Jeremy et al. (2017) Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget 8:16220-16232
Tamura, Akihiro; Hirai, Hideyo; Yokota, Asumi et al. (2017) C/EBP? is required for survival of Ly6C- monocytes. Blood 130:1809-1818
Toska, Eneda; Osmanbeyoglu, Hatice U; Castel, Pau et al. (2017) PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science 355:1324-1330
Shortt, Jake; Ott, Christopher J; Johnstone, Ricky W et al. (2017) A chemical probe toolbox for dissecting the cancer epigenome. Nat Rev Cancer 17:160-183
Gonzalez, David; Luyten, Annouck; Bartholdy, Boris et al. (2017) ZNF143 is an important regulator of the myeloid transcription factor C/EBP?. J Biol Chem :
Tothova, Zuzana; Krill-Burger, John M; Popova, Katerina D et al. (2017) Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell 21:547-555.e8
Valerio, Daria G; Xu, Haiming; Chen, Chun-Wei et al. (2017) Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis. Cancer Res 77:1753-1762
Li, Hubo; Mar, Brenton G; Zhang, Huadi et al. (2017) The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 129:497-508

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