Ravindra Majeti, Postdoctoral Faculty Sponsor
Genome-wide CRISPR screening uncovers potential targets and mechanisms of vincristine resistance in DLBCL.
British journal of haematology
In this issue, Rovsing et al. employ unbiased genome-wide CRISPR screening and functional cellular assays to investigate the cellular response to vincristine, an important component of the front-line DLBCL treatment R-CHOP. Their findings reveal intriguing targets and mechanisms that hold promise for enhancing DLBCL treatment and provide a foundation for the development of future drug regimens. This research prompts further exploration of the translational potential to advance more effective and individualized approaches in the clinical management of DLBCL. Commentary on: Rovsing et al. Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28. Br J Haematol 2023 (Online ahead of print). doi:10.1111/bjh.18872.
View details for DOI 10.1111/bjh.18900
View details for PubMedID 37259613
Impact of standard-dose dipeptidyl peptidase-4 inhibitors on the incidence of graft-versus-host disease after allogeneic hematopoietic cell transplantation
BONE MARROW TRANSPLANTATION
View details for DOI 10.1038/s41409-022-01901-5
View details for Web of Science ID 000903983000001
View details for PubMedID 36572728
Unraveling unique features of plasma cell clones in POEMS syndrome by single-cell analysis.
POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms, including high serum VEGF levels. Since the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. We herein performed the single-cell RNA sequencing of bone marrow plasma cells from patients with POEMS syndrome and identified POEMS clones that had immunoglobulin lambda light chain (IGL) sequences (IGLV1-36, 40, 44, and 47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller (median: 12.9%) than in multiple myeloma (MM) (96-100%) and monoclonal gammopathy of undetermined significance (MGUS) patients (57-81%). Single-cell transcriptomes revealed that POEMS clones were CD19-negative, CD138-positive, and MHC class II-low, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM, accounting for their small size. VEGF mRNA was not up-regulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.
View details for DOI 10.1172/jci.insight.151482
View details for PubMedID 36129760
DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes
2021; 5 (2): 438-450
Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.
View details for DOI 10.1182/bloodadvances.2020001461
View details for Web of Science ID 000613791800011
View details for PubMedID 33496740
View details for PubMedCentralID PMC7839369
Efficacy of the novel tubulin polymerization inhibitor PTC-028 for myelodysplastic syndrome
2020; 111 (12): 4336-4347
Monomer tubulin polymerize into microtubules, which are highly dynamic and play a critical role in mitosis. Therefore, microtubule dynamics are an important target for anticancer drugs. The inhibition of tubulin polymerization or depolymerization was previously targeted and exhibited efficacy against solid tumors. The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC-028, a structural analog of PTC596, for myelodysplastic syndrome (MDS). PTC-028 suppressed growth and induced apoptosis in MDS cell lines. The efficacy of PTC028 in primary MDS samples was confirmed using cell proliferation assays. PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells. Mechanistically, a treatment with PTC-028 induced G2/M arrest followed by apoptotic cell death. We also assessed the efficacy of PTC-028 in a xenograft mouse model of MDS using the MDS cell line, MDS-L, and the AkaBLI bioluminescence imaging system, which is composed of AkaLumine-HCl and Akaluc. PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.
View details for DOI 10.1111/cas.14684
View details for Web of Science ID 000583289000001
View details for PubMedID 33037737
View details for PubMedCentralID PMC7734154
Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma
2019; 24 (1): 52-59
View details for DOI 10.1080/10245332.2018.1509461
View details for Web of Science ID 000451512600001