Browsing by Author "Boyle, Eileen M."

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    Differential RNA splicing as a potentially important driver mechanism in multiple myeloma
    (Ferrata Storti Foundation, 2021-03-01) Bauer, Michael A.; Ashby, Cody; Wardell, Christopher; Boyle, Eileen M.; Ortiz, Maria; Flynt, Erin; Thakurta, Anjan; Morgan, Gareth; Walker, Brian A.; Medicine, School of Medicine
    Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
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    Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
    (Springer, 2022-06-15) Bustoros, Mark; Anand, Shankara; Sklavenitis-Pistofidis, Romanos; Redd, Robert; Boyle, Eileen M.; Zhitomirsky, Benny; Dunford, Andrew J.; Tai, Yu-Tzu; Chavda, Selina J.; Boehner, Cody; Neuse, Carl Jannes; Rahmat, Mahshid; Dutta, Ankit; Casneuf, Tineke; Verona, Raluca; Kastritis, Efstathis; Trippa, Lorenzo; Stewart, Chip; Walker, Brian A.; Davies, Faith E.; Dimopoulos, Meletios-Athanasios; Bergsagel, P. Leif; Yong, Kwee; Morgan, Gareth J.; Aguet, François; Getz, Gad; Ghobrial, Irene M.; Medicine, School of Medicine
    Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models.
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    Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
    (Springer Nature, 2021-12-02) Ghamlouch, Hussein; Boyle, Eileen M.; Blaney, Patrick; Wang, Yubao; Choi, Jinyoung; Williams, Louis; Bauer, Michael; Auclair, Daniel; Bruno, Benedetto; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
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    Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
    (American Association for Cancer Research, 2022) Davies, Faith E.; Pawlyn, Charlotte; Usmani, Saad Z.; San-Miguel, Jesus F.; Einsele, Hermann; Boyle, Eileen M.; Corre, Jill; Auclair, Daniel; Cho, Hearn Jay; Lonial, Sagar; Sonneveld, Pieter; Stewart, A. Keith; Bergsagel, P. Leif; Kaiser, Martin F.; Weisel, Katja; Keats, Jonathan J.; Mikhael, Joseph R.; Morgan, Kathryn E.; Ghobrial, Irene M.; Orlowski, Robert Z.; Landgren, C. Ola; Gay, Francesca; Caers, Joseph; Chng, Wee Joo; Chari, Ajai; Walker, Brian A.; Kumar, Shaji K.; Costa, Luciano J.; Anderson, Kenneth C.; Morgan, Gareth J.; Medicine, School of Medicine
    The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.
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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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    Structural variants shape the genomic landscape and clinical outcome of multiple myeloma
    (Springer Nature, 2022-05-30) Ashby, Cody; Boyle, Eileen M.; Bauer, Michael A.; Mikulasova, Aneta; Wardell, Christopher P.; Williams, Louis; Siegel, Ariel; Blaney, Patrick; Braunstein, Marc; Kaminetsky, David; Keats, Jonathan; Maura, Francesco; Landgren, Ola; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.
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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.