Biology subjects

Vedder, A.

Publications and source records attributed to Vedder, A..

3 recordsLinked to original sources

bioRxiv2022

Targeting BET Proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML

Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development. We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce resistance to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy and credential this using patient-derived xenografts supporting the clinical investigation of this combination.

cancer biology↗

bioRxiv2020

CBL mutations promote activation of PI3K/AKT signaling via LYN kinase

CBL encodes an E3 ubiquitin ligase and signaling adaptor that acts downstream of cytokine receptors. Recurrent CBL mutations occur in myeloid malignancies, but the mechanism by which these mutations drive oncogenesis remains incompletely understood. Here we performed a series of studies to define the phosphoproteome, CBL interactome and molecular mechanisms of signaling activation in cells expressing an allelic series of CBL mutants. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced PIK3R1 recruitment and downstream PI3K/AKT signaling in CBL-mutant cells. Furthermore, we demonstrated in vitro and in vivo efficacy of LYN inhibition by dasatinib in CBL-mutant cell lines and primary chronic myelomonocytic leukemia cells. Overall, our data provide rationale for exploring the therapeutic potential of LYN inhibition in patients with CBL-mutated myeloid malignancies. Statement of SignificanceWe investigated the oncogenic mechanisms of myeloid malignancy-associated CBL mutations by mass spectrometry-based proteomics and interactomics. Our findings indicate that increased LYN kinase activity in CBL-mutant cells stimulates PI3K/AKT signaling, revealing opportunities for the use of targeted inhibitors in CBL-mutated myeloid malignancies.

cancer biology↗

bioRxiv2019

RAS mutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

ABSTRACTChronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with limited treatment options. Whole exome (WES) and targeted sequencing of several independent cohorts of CMML patients, comparing dysplastic (dCMML) to proliferative (pCMML) CMML, as well as paired chronic phase disease and acute leukemic transformation (LT), associate acquisition of oncogenic RAS pathway mutations, the most common being NRASG12D, with aggressive disease and with disease progression. Using patient derived progenitor colony assays and a NRASG12D-Vav-Cre mouse model, we further demonstrate the role of mutant RAS signaling in driving and maintaining pCMML phenotype. RNA-sequencing links RAS pathway mutations with an increased expression of genes encoding the mitotic checkpoint kinases PLK1 and WEE1. Further, we dmeoinstrated that non-mutated lysine methyltransferase KMT2A (MLL1) acts as mediator of NRAS-induced PLK1 and WEE1 expression. Finally, we demonstrate the translational value of our findings by showing that pharmacological PLK1 inhibition decreases monocytosis and hepatosplenomegaly while improving hematopoiesis in RAS mutant patient-derived xenografts. Hence, we define severe CMML as oncogenic RAS pathway-enriched malignancies, with a unique gene expression profile regulated by KMT2A, amenable to therapeutic intervention.

cancer biology↗