CBL mutations are common in chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), myelodysplastic syndrome, and clonal hematopoiesis of indeterminate potential (CHIP). CBL is an E3 ubiquitin ligase that recognizes phosphorylated receptor tyrosine kinases (RTKs) and mediates both downstream signaling and destruction of activated RTKs that are critical for leukemogenesis, including KIT, FLT3 and CSF2RB. (1, 2) There are no therapies that specifically address CBL-mutant leukemia, an ideal target for genotype-directed therapy. CBL is a central node for kinase signaling, and unlike most common mutations in leukemia, CBL mutations result in a gain-of-function, activating specific signaling pathways. CBL-mediated ubiquitination of activated tyrosine kinases triggers their proteasomal degradation, a negative feedback for ongoing signaling. In leukemia, CBL mutations specifically abolish the ubiquitin ligase activity, leaving CBL- mediated downstream signaling unchecked, resulting in prolonged kinase signaling and increased cellular proliferation. The central goal of this proposal is to understand the mechanistic basis of CBL mutations in order to identify the set of proteins and pathways that are dysregulated and can be targeted for the treatment of CBL- mutant leukemia.
In Aim 1, we will determine the specific phosphorylated proteins that are degraded by CBL in leukemia cells and stabilized when CBL is mutated, leading to constitutive signaling. Mechanistically, we will examine how specific point mutations in CBL alter the binding and ubiquitination of substrates, and the initiation of downstream signaling.
In Aim 2, we will investigate the combinations of kinase inhibitors with greatest therapeutic potential using both in vitro and in vivo models. Preliminary studies highlight the aberrant activation of LYN kinase and PI3K/AKT signaling pathways in cells with CBL RING domain mutations. We hypothesize that inhibiting these signaling pathways, and other kinases identified in Aim 1, will selectively target CBL-mutant cells and may have therapeutic activity in CBL-mutant myeloid malignancies. We will develop and characterize in vivo models of CMML with Cbl mutations, and test the efficacy of FDA approved drugs, dasatinib and dactolisib, alone and in combination.
In Aim 3, we will investigate the biology of the CRL5CISH ubiquitin ligase. Preliminary studies identified CRL5CISH ubiquitin ligase as a potential reserve for CBL, regulating an overlapping set of signaling pathways, but also degrading key signaling molecules that are not degraded by CBL. We will examine the biology of this CRL5CISH ubiquitin ligase in CBL wild-type and mutant cells. Manipulation of the activity of this ubiquitin ligase could alter ubiquitination of substrates that are aberrantly regulated in CBL-mutant leukemias. Overall, this project will elucidate the biology and therapeutic vulnerabilities in CBL-mutant leukemia. The project will leverage the expertise in ubiquitin ligase biology in the Ebert laboratory and across the P01. Since the pathways that are activated in CBL-mutant leukemias are signaling pathways, the recent development of drugs that target protein kinases will enable rapid clinical translation of the findings.
Mutations in the CBL gene are common in leukemia, but there are currently no therapies specifically for patients with mutations in this gene. CBL mutations create opportunities for targeted therapy because these mutations lead to activation of signaling pathways that can be inhibited by FDA-approved drugs. We will identify the pathways that are activated when CBL is mutated, characterize the biology of these mutations, and test candidate therapies for CBL-mutant leukemia.
|Wroblewski, Mark; Scheller-Wendorff, Marina; Udonta, Florian et al. (2018) BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells. Haematologica 103:939-948|
|Konopleva, Marina; Letai, Anthony (2018) BCL-2 inhibition in AML: an unexpected bonus? Blood 132:1007-1012|
|Donovan, Katherine A; An, Jian; Nowak, Rados?aw P et al. (2018) Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife 7:|
|Lee, J Scott; Roberts, Andrew; Juarez, Dennis et al. (2018) Statins enhance efficacy of venetoclax in blood cancers. Sci Transl Med 10:|
|Liu, Bee Hui; Jobichen, Chacko; Chia, C S Brian et al. (2018) Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proc Natl Acad Sci U S A 115:E7119-E7128|
|Kahn, Josephine D; Miller, Peter G; Silver, Alexander J et al. (2018) PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095-1105|
|Libby, Peter; Ebert, Benjamin L (2018) CHIP (Clonal Hematopoiesis of Indeterminate Potential). Circulation 138:666-668|
|Wolach, Ofir; Sellar, Rob S; Martinod, Kimberly et al. (2018) Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med 10:|
|Kelly, Rachel S; Lasky-Su, Jessica; Yeung, Sai-Ching J et al. (2018) Integrative omics to detect bacteremia in patients with febrile neutropenia. PLoS One 13:e0197049|
|Hogan, Louise E; Körner, Christian; Hobbs, Kristen et al. (2018) NK-cell activation is associated with increased HIV transcriptional activity following allogeneic hematopoietic cell transplantation. Blood Adv 2:1412-1416|
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