Hannah Cheung Beird

University of Texas MD Anderson Cancer Center | MD Anderson · Department of Genomic Medicine

Desmoplastic small round cell tumor (DSRCT) is a rare and usually incurable aggressive sarcoma subtype affecting both adults and young adolescents. All tumor cells harbor a pathognomonic EWS::WT1 fusion protein (FP), but FP-targeted agents are nonexistent. Less than 20% of patients survive beyond five years with standard of care. Our work showed th...

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therap...

Objectives We sought to investigate the morphologic and immunophenotypic characteristics of TCL1 family–negative T-cell prolymphocytic leukemia (T-PLL) Methods Twenty cases of TCL1 family–negative T-PLL were studied. Results The doubling time of leukemic cells ranged from less than 2 days to more than 5 years, with a median of 5.5 months. Leukemi...

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα si...

11546 Background: Leiomyosarcomas (LMS) are aggressive malignancies of smooth-muscle origin. Few targeted molecular options exist and immunotherapy (IO) agents against T cells have been disappointing. In this study, we examine the immune infiltrate of LMS tumors by immunohistochemistry (IHC) and gene expression. Our objective was to identify action...

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR targeted treatments. Therefore, we designed a protein and genomic based RNase H2 screening assay to determine its prevalence and prognostic significa...

Osteosarcoma (OS) manifests during puberty, coinciding with rapid bone growth, a feature requiring exploration. We selectively deleted p53 or both p53 and Rb1 alleles in growth-dependent chondrocyte-origin models, utilizing Col10a1-Cre or Agc-CreERT2, incorporating with ROSA-Tomato for tracing and isolating the mutant cell collection. Col10p53flfl(...

Cardiac angiosarcoma (CAS) is an extremely rare malignant cardiac tumor known for its propensity for early metastasis and poor prognosis. CAS frequency is around 1-2% of all angiosarcoma cases and mostly arise in the right atrium. At present, there are no effective treatments and the survival rate is less than 10% at 5 years. Furthermore, the deart...

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma subtype that is usually uncurable. All malignant cells harbor a pathognomonic EWSR1::WT1 fusion protein (FP), but FP-targeted agents are nonexistent, and less than 20% of patients survive beyond five years. Lacking the availability of FP-targeted drugs, we seek to understa...

Gene disruption from double‐strand DNA breaks within introns is a mechanism of inactivating the tumor suppressor TP53 . This occurs more frequently in osteosarcoma and biliary adenocarcinoma compared with other cancer types. The patterns of intron breakpoints within TP53 do not correlate with prevalence, intron length, or overall genome‐wide levels...

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 p...

Desmoplastic small round cell tumor (DSRCT) is a rare, usually incurable, aggressive sarcoma subtype that occurs predominantly in adolescent and young adult (AYA) males. At diagnosis, most present with hundreds of intraabdominal nodules composed of malignant cells that harbor a EWSR1-WT1 chromosomal translocation and resultant fusion protein (FP)....

11549 Background: Targeting the DNA damage response (DDR)/Homologous Recombination (HR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS). Loss of RNase H2 decreases DNA repair via the Non-Homologous End-Joining (NHEJ) pathway, leading to increased double stranded breaks, replication stress, and increased cell death. Therefore, w...

Unlabelled: Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 2...

Background: Adult-type granulosa cell tumors (AGCT) are rare ovarian sex cord tumors that exhibit near-universal FOXL2 c.C402G (p.Cys134Trp) hotspot mutations. AGCT recurrence is difficult to predict and is almost always incurable after relapse. Little is known about the relationship between intra-tumor immune and stromal composition and AGCT relap...

Desmoplastic small round cell tumor (DSRCT) is a rare, usually incurable, aggressive sarcoma subtype that occurs predominantly in adolescent and young adult (AYA) males. At diagnosis, most present with hundreds of intraabdominal nodules composed of malignant cells that harbor a EWSR1-WT1 chromosomal translocation and resultant fusion protein (FP)....

Among the many sarcoma subtypes, high-grade tumors that have failed to differentiate or undergone dedifferentiation strongly correlate with metastatic potential and poor clinical outcomes. To examine the factors that regulate cell fate, lineage plasticity, and tumor grade, we focused on two common liposarcoma variants, dedifferentiated liposarcoma...

T-prolymphocytic leukemia (T-PLL) is a rare mature T-cell neoplasm defined by rearrangements involving TCL1 or MTCP1 . Cases showing some overlapping features with T-PLL but lacking TCL1 and MTCP1 rearrangements have been rarely reported but are not well characterized. Whether these neoplasms belong within the category of T-PLL or represent a disti...

Soft tissue sarcomas STS are malignancies that show mesenchymal and neuroectodermal differentiation and thus most often resemble supportive and connective tissue including fat blood vessels muscle bone tendons and nerves Over 70 subtypes of sarcomas exist and pathologists have classified these broadly according to the degree to which they resemble...

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While ther...

There is scant information on the clinical progression, end-of-life decisions, and cause of death of patients with cancer diagnosed with COVID-19. Therefore, we conducted a case series of patients admitted to a comprehensive cancer center who did not survive their hospitalization. To determine the cause of death, 3 board-certified intensivists revi...

In a subset of acute myeloid leukemia (AML) cases, the core binding factor beta subunit gene (CBFB) was rearranged via inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in which the smooth muscle myosin heavy chain 11 gene (MYH11) was the partner (CBFB::MYH11). Rare variants of CBFB rearrangement occurring via non-classic chromosomal aberrations have been...

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstr...

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specime...

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstr...

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profili...

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components—SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neura...

B‐cell lymphoma/leukaemia 11B (BCL11B) is an essential transcription factor for T‐cell lineage commitment and maturation. We investigated BCL11B expression by immunohistochemistry in T‐lymphoblastic leukaemia/lymphoma (T‐ALL/LBL) (n = 115). The majority (83%) of early T‐cell precursor T‐ALL/LBL (ETP‐ALL) cases showed negative BCL11B expression, whi...

Sarcomas encompass a rare but highly diverse set of tumor malignancies, contributing disproportionately to years of life lost. Immune checkpoint blockade (ICB) has been successful across various tumor types; however, their efficacy and predictability in sarcomas remain unknown. We conducted a translational study using pre- and on-treatment tumor bi...

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation bet...

Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutat...

Brain metastases (BM) occur in 10-30% of patients with cancer. Approximately 200,000 new cases of brain metastases are diagnosed in the United States annually, with median survival after diagnosis ranging from 3 to 27 months. Recently, studies have identified significant genetic differences between BM and their corresponding primary tumors. It has...

Chemotherapy/ targeted therapy are both known to trigger evolution of treatment resistant clones that can lead to relapse. Allogeneic stem cell transplant (alloSCT) for refractory Chronic Lymphocytic Leukemia (CLL) patients is associated with better outcomes. We hypothesized that allogeneic T-cell immunotherapies, including alloSCT and donor lympho...

Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatri...

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant hematologic malignancy with poor outcomes and with just one recently approved agent (tagraxofusp). It is characterized by the abnormal proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (...

Background: BPDCN is a clinically aggressive myeloid malignancy that has historically demonstrated poor outcomes. Recent patho-biological observations have led to new therapies and improved outcomes, including the first approved therapy in the field with CD123-directed therapy (Pemmaraju et al. NEJM April 2019). BPDCN is recognized for its overexpr...

Notch signaling pathway is a mediator of cell differentiation and is critical for normal bone development. Four functional Notch ligands DLL1 and DLL4, and JAG1 and JAG2 showed various levels of affinity for Notch1-4 receptors. Dose dependent Notch signaling activation or blocking is attributed to anchored or soluble form of Notch ligands binding....

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic neoplasm involving skin lesions and disseminated disease into bone marrow, peripheral blood, and lymph nodes, characterized by poor clinical outcomes and no standard therapeutic approaches. BPDCN is characterized by the malignant proliferation of precursor plasma...

Osteosarcoma (OS) is characterized by genomic complexity and significant genetic heterogeneity. However, it is unknown whether relapse and metastatic samples incur additional insults to genomic integrity. To examine this, we conducted in-depth genomic profiling in a cohort of 48 pediatric and adult patients with high-grade OS including 42 patients...

Numerous gene fusions have been uncovered across multiple cancer types. Although the ability to target several of these fusions has led to the development of some successful anti-cancer drugs, most of them are not druggable. Understanding the molecular pathways of a fusion is important in determining its function in oncogenesis and in developing th...

Evaluation of FUS-DDIT3 prediction using data-driven gene signatures that are associated with Trabectedin. The four data-driven gene signatures associated with Trabectedin were collected from several previous works (detailed in S4 Text). (TIFF)

Top 10% BCR-ABL1- associated genes that are significantly up-regulated upon imatinib treatment. (DOCX)

Compounds that have been in clinical trials and used for treatment of Ewing’s sarcoma. We complied 67 target genes of 22 drugs that have been already in clinical trials and used for treatment of Ewing’s sarcoma from several review papers and drug databases (detailed in S3 Text). (DOCX)

Sensitive compounds for myxoid liposarcoma cell lines and their target genes. 48 sensitive compounds were identified in three Myxoid liposarcoma cell lines (MLS-1765-92, MLS-402-91, and MLS-DL221) using the high-throughput screening assay. Target genes of these sensitive compounds were complied from available public databases, and 38 of the 48 comp...

Supporting information for the BCR-ABL1 prediction. (DOCX)

Supporting information for the FUS-DDIT3 prediction. (DOCX)

Bar plot of some statistically significant pathways that are associated with FUS-DDIT3 in our prediction. A bar in the graph represents the statistically significance of a given pathway in GSEA association analysis, GSEA deregulation analysis, or combination analysis using the truncated product method. The statistically significances are presented...

Sensitive compounds for Ewing’s sarcoma cell lines and their target genes. 76 sensitive compounds were identified in two Ewing’s sarcoma cell lines (TC32 and TC71) using the high-throughput screening assay. Target genes of these sensitive compounds were complied from available public databases, and 60 of the 76 compounds have known target genes. To...

Supporting information for network data and drug screens. (DOCX)

Supporting information for the EWS-FLI1 prediction. (DOCX)

Prediction evaluation Of BCR-ABL1 using data-driven gene signatures. The three data-driven gene signatures were collected from several previous works (detailed in S2 Text). (TIFF)

Prediction evaluation of BCR-ABL1 variants using the four benchmark gene sets. The three known BCR-ABL1 variants are denoted “p185”, “p210”, and “p230” respectively. (a) genes co-cited with BCR-ABL1 in literature. (b) CML associated genes. (c) target genes of drugs that have been already in clinical trials or used for treatment of CML (d) 26 Wnt/Ca...

Bar plot of some statistically significant pathways that are associated with EWS-FLI1 in our prediction. A bar in the graph represents the statistically significance of a given pathway in GSEA association analysis, GSEA deregulation analysis, or combination analysis using the truncated product method. The statistically significances are presented i...

Prediction evaluation of EWS-FLI1 using data-driven gene signatures that are associated with EWS-FLI1 or Ewing’s sarcoma. The four data-driven gene signatures were collected from several previous works (detailed in S3 Text). (TIFF)

Compounds that have been in clinical trials or used for treatment of CML. We complied 68 target genes of 24 compounds that have been already in clinical trials and used for treatment of CML from several review papers and drug databases (detailed in S2 Text). (DOCX)

Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that tr...

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define us...

Well-differentiated/dedifferentiated liposarcoma is a common soft tissue sarcoma with approximately 1500 new cases per year. Surgery is the mainstay of treatment but recurrences are frequent and systemic options are limited. 'Tumor genotyping' is becoming more common in clinical practice as it offers the hope of personalized targeted therapy. We wa...

Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and...