Browsing by Author "Barlogie, Bart"

Now showing 1 - 4 of 4
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    PHF19 inhibition as a therapeutic target in Multiple Myeloma
    (Elsevier, 2021) Schinke, Carolina D.; Bird, Jordan T.; Qu, Pingping; Yaccoby, Shmuel; Lyzogubov, Valeriy V.; Shelton, Randal; Ling, Wen; Boyle, Eileen M.; Deshpande, Sharyu; Byrum, Stephanie D.; Washam, Charity; Mackintosh, Samuel; Stephens, Owen; Thanendrarajan, Sharmilan; Zangari, Maurizio; Shaughnessy, John, Jr.; Zhan, Fenghuang; Barlogie, Bart; van Rhee, Frits; Walker, Brian A.; Medicine, School of Medicine
    Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.
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    Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups
    (Springer, 2022-02) Boyle, Eileen M.; Rosenthal, Adam; Ghamlouch, Hussein; Wang, Yan; Farmer, Phillip; Rutherford, Michael; Ashby, Cody; Bauer, Michael; Johnson, Sarah K.; Wardell, Christopher P.; Wang, Yubao; Hoering, Antje; Schinke, Carolina; Thanendrarajan, Sharmilan; Zangari, Maurizio; Barlogie, Bart; Dhodapkar, Madhav V.; Davies, Faith E.; Morgan, Gareth J.; van Rhee, Frits; Walker, Brian A.; Medicine, School of Medicine
    Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
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    The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma
    (Springer Nature, 2021-01-12) Boyle, Eileen M.; Deshpande, Shayu; Tytarenko, Ruslana; Ashby, Cody; Wang, Yan; Bauer, Michael A.; Johnson, Sarah K.; Wardell, Christopher P.; Thanendrarajan, Sharmilan; Zangari, Maurizio; Facon, Thierry; Dumontet, Charles; Barlogie, Bart; Arbini, Arnaldo; Rustad, Even H.; Maura, Francesco; Landgren, Ola; Zhan, Fenghuang; van Rhee, Frits; Schinke, Carolina; Davies, Faith E.; Morgan, Gareth J.; Walker, Brian A.; Medicine, School of Medicine
    Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
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    The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
    (Springer, 2022-08-03) Rasche, Leo; Schinke, Carolina; Maura , Francesco; Bauer , Michael A.; Ashby, Cody; Deshpande , Shayu; Poos , Alexandra M.; Zangari , Maurizio; Thanendrarajan, Sharmilan; Davies, Faith E.; Walker, Brian A.; Barlogie, Bart; Landgren, Ola; Morgan, Gareth J.; van Rhee, Frits; Weinhold , Niels; Medicine, School of Medicine
    Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.