Hematology Commons^™

Protein S In Coagulation And Inflammation, Martha Mega Silvia Sim

Theses and Dissertations--Molecular and Cellular Biochemistry

Protein S (PS) is a key regulator, which links inflammation and coagulation and performs multiple proposed functions in both processes. PS exists in the blood as a free soluble form (~40%), bound to complement component 4b-binding protein/ C4BP (~60%), and packaged in platelet α-granules (~2.5%). Subendothelial tissue factor (TF), upon exposure to blood, initiates coagulation, a proteolytic cascade which results in the activation of thrombin, the enzyme responsible for formation of a fibrin clot. PS is a critical anticoagulant that inhibits multiple steps of this process. Only the free fraction of PS has full anticoagulant properties, as C4BP blocks this …

Positron Emission Tomography Derived Metrics In Relapsed Or Refractory Large B-Cell Lymphoma With Residual Disease Before Autologous Stem Cell Transplant, Hua-Jay J Cherng, Guofan Xu, Lei Feng, Raphael Steiner, Luis Fayad, Paolo Strati, Ranjit Nair, Loretta J Nastoupil, Hun Ju Lee, Sattva S Neelapu, Christopher R Flowers, Maria Rodriguez, Michael Wang, Fredrick Hagemeister, Chelsea C Pinnix, Jeremy Ramdial, Samer Srour, Yago Nieto, Katayoun Rezvani, Richard Champlin, Partow Kebriaei, Jason Westin, Homer A Macapinlac, Elizabeth Shpall, Sairah Ahmed

Faculty, Staff and Student Publications

Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A18 F-fluorodeoxyglucose positron emission tomography (PET) scan after salvage chemotherapy is used to assess response and eligibility for ASCT, but metrics for chemosensitivity in patients with residual disease are not well defined. We performed a single-centre retrospective analysis of 92 patients with a partial response or stable disease after salvage chemotherapy for rrLBCL who received ASCT to investigate PET-derived parameters and their prognostic utility. The Deauville 5-point Scale (D-5PS) score, …

Improved Outcomes With “7+3” Induction Chemotherapy For Acute Myeloid Leukemia Over The Past Four Decades: Analysis Of Swog Trial Data, Megan Othus, Guillermo Garcia-Manero, John E Godwin, James K Weick, Frederick R Appelbaum, Harry P Erba, Elihu H Estey

Faculty, Staff and Student Publications

We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from …

Development And Validation Of Early Death Risk Score Model For Emergency Status Prediction In Very Severe Aplastic Anemia, Xu Liu, Wenrui Yang, Li Zhang, Liping Jing, Lei Ye, Kang Zhou, Yuan Li, Jianping Li, Huihui Fan, Yang Yang, Youzhen Xiong, Xin Zhao, Fengkui Zhang

Faculty, Staff and Student Publications

This study developed and validated the Early Death Risk Score Model for early identification of emergency patients with very severe aplastic anemia (VSAA). All 377 patients with VSAA receiving first-line immunosuppressive therapy (IST) were categorized into training (n=252) and validation (n=125) cohorts. In the training cohort, age >24 years, absolute neutrophil count ≤0.015×109/L, serum ferritin >900ng/mL and times of fever before IST >1 time were significantly associated with early death. Covariates were assigned scores and categorized as: low (score 0-4), medium (score 5-7) and high (score ≥8) risk. Early death rate was significantly different between risk groups and the validation …

The History Of Oral Decitabine/Cedazuridine And Its Potential Role In Acute Myeloid Leukemia, Robert Briski, Guillermo Garcia-Manero, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Decitabine, a member of the 5-azanucleosides, has a dose-dependent mechanism of action in vitro: termination of DNA replication at high doses, and inhibition of DNA methyltransferase at low doses. The alteration of DNA methylation patterns by low-dose decitabine is hypothesized to upregulate genes, which promote myeloblast differentiation. In a phase III clinical trial, low-dose decitabine achieved a superior overall response rate (ORR) when compared with 'treatment choice' [consisting of low-dose cytarabine (80%) and supportive care (20%)] as a frontline treatment for elderly patients with acute myeloid leukemia (AML). Despite an improved ORR, the median overall survival (OS) for elderly …

Survival Outcomes In Patients With Relapsed/Refractory Or Mrd-Positive B-Cell Acute Lymphoblastic Leukemia Treated With Blinatumomab, Hagop M Kantarjian, Aaron C Logan, Faraz Zaman, Nicola Gökbuget, Ralf C Bargou, Yi Zeng, Gerhard Zugmaier, Franco Locatelli

Faculty, Staff and Student Publications

Blinatumomab has demonstrated significant efficacy in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-cell ALL) and patients with measurable residual disease (MRD). This review aimed to compare median relapse-free survival (RFS) and median overall survival (OS) in adult and pediatric patients with R/R or MRD-positive B-cell ALL from pivotal studies [MT-103-211 and TOWER for adults with Philadelphia chromosome (Ph)-negative R/R B-cell ALL, ALCANTARA for adults with Ph-positive R/R B-cell ALL, MT-103-203 for adults with MRD-positive B-cell ALL, and MT-103-205 for pediatric patients with R/R B-cell ALL], with the median RFS and OS from retrospective analyses, country …

การศึกษาลักษณะกลายพันธุ์ของยีนที่ถอดรหัสเป็นโปรตีนในเยื่อหุ้มเซลล์เม็ดเลือดแดงในผู้ป่วยกลุ่มเยื่อหุ้มเซลล์เม็ดเลือดแดงผิดปกติ, จารุวรรณ ปานาราช

Chulalongkorn University Theses and Dissertations (Chula ETD)

โรคกลุ่มเยื่อหุ้มเซลล์เม็ดเลือดแดงผิดปกติเป็นโรคโลหิตจางตั้งแต่กำเนิดเกิดจากการกลายพันธุ์ของยีนที่กำหนดการสร้างโปรตีนไซโทสเกเลตอนซึ่งเป็นโครงสร้างของเยื่อหุ้มเซลล์เม็ดเลือดแดงเพื่อให้เซลล์เม็ดเลือดแดงมีความยืดหยุ่นและรักษารูปร่างได้โดยยีนที่เกี่ยวข้องได้แก่ ANK1, SPTA1, SPTB, EPB42 และ SLC4A1 งานวิจัยนี้ทำการศึกษาการกลายพันธุ์โดยใช้ Whole exome sequence (WES) และตรวจยืนยันผลด้วยเทคนิค Sanger sequencing ซึ่งงานวิจัยนี้พบการกลายพันธุ์ตำแหน่งใหม่ที่เป็นสาเหตุทำให้เกิดโรคเม็ดเลือดแดงป่องพันธุกรรมจำนวน 3 ตำแหน่งและพบการกลายพันธุ์ในผู้ป่วย hereditary pyropoikilocytosis (HPP) 1 ตำแหน่ง การกลายพันธุ์ตำแหน่งใหม่ประกอบด้วยการกลายพันธุ์ในยีน SPTB ตำแหน่ง c.5692C>T และ c.3823delG และในยีน ANK1 c.1994C>A ผลการศึกษาผลของการกลายพันธุ์ในระดับอาร์เอ็นเอพบว่าการกลายพันธุ์ตำแหน่ง c.5692C>T และ c.3823delG ในยีน SPTB และ c.1994C>A ในยีน ANK1 ส่งผลให้เกิด premature stop codon และพบว่าการกลายพันธุ์ตำแหน่ง c.5692C>T และ c.3823delG ในยีน SPTB ส่งผลให้ระดับการแสดงออกของยีนลดลงเมื่อเทียบกับคนปกติซึ่งอาจเกิดจากกระบวนการ nonsense-mediated mRNA degradation ทำให้ mRNA ที่ผิดปกติถูกทำลาย ผลจากการเพาะเลี้ยงเซลล์เม็ดเลือดตัวอ่อนพบว่าผู้ป่วยเม็ดเลือดแดงป่องพันธุกรรมมีอัตราการเพิ่มจำนวนเซลล์เม็ดเลือดแดงตัวอ่อนมากกว่าคนปกติ แต่มีการเจริญเติบโตและพัฒนาช้ากว่าคนปกติ จากการวัดปริมาณไมโครพาติเคิลด้วยเทคนิคโฟลไซโทเมทรีพบว่าในผู้ป่วยกลุ่มเยื่อหุ้มเซลล์เม็ดเลือดแดงผิดปกติมีปริมาณไมโครพาติเคิลที่สูงกว่าคนปกติ องค์ความรู้ที่ได้จากงานวิจัยนี้ทำให้ทราบกลไกการเกิดความผิดที่เกิดจากการกลายพันธุ์ของยีน SPTB และ ANK1 ในเซลล์เม็ดเลือดแดงผู้ป่วยกลุ่มเยื่อหุ้มเซลล์เม็ดเลือดแดงผิดปกติเพิ่มขึ้น

Hyperviscosity Syndrome Induced Bilateral Visual And Auditory Impairment In Therapy Resistant Waldenström Macroglobulinemia With Myd88 And Cxcr4 Mutations, Marie M Plante, Erinmarie O Kimbrough, Amit K Agarwal, Liuyan Jiang, Kirk Bourgeois, Greta C Stamper, Michael W Stewart, Han W Tun

Faculty, Staff and Student Publications

Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib …

Antithrombin Activity Is Associated With Persistent Thromboinflammation And Mortality In Patients With Severe Covid-19 Illness, Amber Chen-Goodspeed, Goutham Dronavalli, Xu Zhang, Jeanette M Podbielski, Bela Patel, Katalin Modis, Bryan A Cotton, Charles E Wade, Jessica C Cardenas

Faculty, Staff and Student Publications

Introduction: Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients.

Methods: This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and …

Treatment De-Escalation In Philadelphia Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia: The Emerging Role Of Chemotherapy-Free Regimens, Fadi G Haddad, Jacki Sawyers, Nicholas J Short

Faculty, Staff and Student Publications

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many …

Strengthening Deep-Learning Models For Intracranial Hemorrhage Detection: Strongly Annotated Computed Tomography Images And Model Ensembles, Dong-Wan Kang, Gi-Hun Park, Wi-Sun Ryu, Dawid Schellingerhout, Museong Kim, Yong Soo Kim, Chan-Young Park, Keon-Joo Lee, Moon-Ku Han, Han-Gil Jeong, Dong-Eog Kim

Faculty, Staff and Student Publications

BACKGROUND AND PURPOSE: Multiple attempts at intracranial hemorrhage (ICH) detection using deep-learning techniques have been plagued by clinical failures. We aimed to compare the performance of a deep-learning algorithm for ICH detection trained on strongly and weakly annotated datasets, and to assess whether a weighted ensemble model that integrates separate models trained using datasets with different ICH improves performance.

METHODS: We used brain CT scans from the Radiological Society of North America (27,861 CT scans, 3,528 ICHs) and AI-Hub (53,045 CT scans, 7,013 ICHs) for training. DenseNet121, InceptionResNetV2, MobileNetV2, and VGG19 were trained on strongly and weakly annotated datasets and …

Risk Factors And Prognostic Significance Of Anemia In Children With Hiv Infection On Antiretroviral Therapy, Joseph Lubega, Amanda Grimes, Gladstone Airewele, Shaun Bulsara, Taylor Olmsted Kim, Heather Haq, Erin Peckham-Gregory, Sebastian R Wanless, Peter Elyanu, Philippa Musoke, Mwita Lumumba, Adeodata Kekitiinwa, Mogomotsi Matshaba, Jenny Despotovic, Michael Scheurer

Faculty, Staff and Students Publications

OBJECTIVES: To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH).

DESIGN: Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014.

METHODS: Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival.

RESULTS: Two thousand, one hundred and thirty-seven children were …

Clinical And Molecular Profiling Of Aml Patients With Chromosome 7 Or 7q Deletions In The Context Of Tp53 Alterations And Venetoclax Treatment, Hussein A Abbas, Edward Ayoub, Hanxiao Sun, Rashmi Kanagal-Shamanna, Nicholas J Short, Ghayas Issa, Musa Yilmaz, Sherry Pierce, Daniel Rivera, Brent Cham, Shane Wing, Ziyi Li, Danielle Hammond, Elias Jabbour, Gautam Borthakur, Guillermo Garcia-Manero, Michael Andreeff, Naval Daver, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Farhad Ravandi

Faculty, Staff and Student Publications

Deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events in acute myeloid leukemia (AML). We retrospectively analyzed 243 treatment-naive patients with AML and del(7) (168/243; 69%) or del(7q) (75/243; 31%) who did not receive any myeloid-directed therapy prior to AML diagnosis. This is the largest comprehensive clinical and molecular analysis of AML patients with del(7) and del(7q). Our results show that relapse-free survival was significantly longer for AML patients with del(7q) compared to del(7), but the overall survival and remission duration were similar. TP53 mutations and del5/5q were the most frequent co-occurring …

Implications Of Ras Mutational Status In Subsets Of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes, Daniel Rivera, Kunhwa Kim, Rashmi Kanagal-Shamanna, Gautam Borthakur, Guillermo Montalban-Bravo, Naval Daver, Courtney Dinardo, Nicholas J Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with …

Association Of Hematologic Response And Assay Sensitivity On The Prognostic Impact Of Measurable Residual Disease In Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Nicholas J Short, Chenqi Fu, Donald A Berry, Roland B Walter, Sylvie D Freeman, Christopher S Hourigan, Xuelin Huang, Graciela Nogueras Gonzalez, Hyunsoo Hwang, Xinyue Qi, Hagop Kantarjian, Shouhao Zhou, Farhad Ravandi

Faculty, Staff and Student Publications

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was …

Mdm2 Antagonist Improves Therapeutic Activity Of Azacitidine In Myelodysplastic Syndromes And Chronic Myelomonocytic Leukemia, Yue Wei, Hong Zheng, Pamela Pennington Lockyer, Faezeh Darbaniyan, Ziyi Li, Rashmi Kanagal-Shamanna, Kelly A Soltysiak, Hui Yang, Irene Ganan-Gomez, Guillermo Montalban-Bravo, Kelly S Chien, Kim-Anh Do, Naval Daver, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Pathogenicity And Impact Of Hla Class I Alleles In Aplastic Anemia Patients Of Different Ethnicities, Timothy S Olson, Benjamin F Frost, Jamie L Duke, Marian Dribus, Hongbo M Xie, Zachary D Prudowsky, Elissa Furutani, Jonas Gudera, Yash B Shah, Deborah Ferriola, Amalia Dinou, Ioanna Pagkrati, Soyoung Kim, Yixi Xu, Meilun He, Shannon Zheng, Sally Nijim, Ping Lin, Chong Xu, Taizo A Nakano, Joseph H Oved, Beatriz M Carreno, Yung-Tsi Bolon, Shahinaz M Gadalla, Steven Ge Marsh, Sophie Paczesny, Stephanie J Lee, Dimitrios S Monos, Akiko Shimamura, Alison A Bertuch, Loren Gragert, Stephen R Spellman, Daria V Babushok

Department of Medicine Faculty Papers

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we …

Phase Ii Study Of Venetoclax Added To Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine In Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Tapan M Kadia, Patrick K Reville, Xuemei Wang, Caitlin R Rausch, Gautam Borthakur, Naveen Pemmaraju, Naval G Daver, Courtney D Dinardo, Koji Sasaki, Ghayas C Issa, Maro Ohanian, Guillermo Montalban-Bravo, Nicholas J Short, Nitin Jain, Alessandra Ferrajoli, Kapil N Bhalla, Elias Jabbour, Koichi Takahashi, Rashmi Malla, Kelly Quagliato, Rashmi Kanagal-Shamanna, Uday R Popat, Michael Andreeff, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

PURPOSE: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.

METHODS: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with …

Preclinical Evaluation Of Combination Nemtabrutinib And Venetoclax In Chronic Lymphocytic Leukemia, Elizabeth M Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A Rogers, John C Byrd, Jennifer A Woyach

Faculty, Staff and Student Publications

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and …

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

Targeting The Eif2ak1 Signaling Pathway Rescues Red Blood Cell Production In Sf3b1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts, Vera Adema, Feiyang Ma, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guillermo Montalban-Bravo, Hui Yang, Scott A Peslak, Feng Wang, Pamela Acha, Francesc Sole, Pamela Lockyer, Margherita Cassari, Jaroslaw P Maciejewski, Valeria Visconte, Irene Gañán-Gómez, Yuanbin Song, Carlos Bueso-Ramos, Matteo Pellegrini, Tuyet M Tan, Rafael Bejar, Jennifer S Carew, Stephanie Halene, Valeria Santini, Gheath Al-Atrash, Karen Clise-Dwyer, Guillermo Garcia-Manero, Gerd A Blobel, Simona Colla

Faculty, Staff and Student Publications

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of …

Tp53-Mutated Myelodysplastic Syndrome And Acute Myeloid Leukemia: Biology, Current Therapy, And Future Directions, Naval G Daver, Abhishek Maiti, Tapan M Kadia, Paresh Vyas, Ravindra Majeti, Andrew H Wei, Guillermo Garcia-Manero, Charles Craddock, David A Sallman, Hagop M Kantarjian

Faculty, Staff and Student Publications

UNLABELLED: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches …

Stroke Genetics Informs Drug Discovery And Risk Prediction Across Ancestries, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel C Posner, Frederick K Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K Georgakis, Ilana Caro, Kristi Krebs, Yi-Ching Liaw, Felix C Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee-Joon Bae, Ganesh Chauhan, Michael R Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Marianne Nygaard, Hampton L Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J Knol, Adam J Lewis, Renae L Judy, Tetsuro Ago, Philippe Amouyel, Nicole D Armstrong, Mark K Bakker, Traci M Bartz, David A Bennett, Joshua C Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W Cole, Phil L De Jager, Rafael De Cid, Matthias Endres, Leslie E Ferreira, Mirjam I Geerlings, Natalie C Gasca, Vilmundur Gudnason, Jun Hata, Jing He, Alicia K Heath, Yuk-Lam Ho, Aki S Havulinna, Jemma C Hopewell, Hyacinth I Hyacinth, Michael Inouye, Mina A Jacob, Christina E Jeon, Christina Jern, Masahiro Kamouchi, Keith L Keene, Takanari Kitazono, Steven J Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J Launer, Keon-Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S Markus, Nicholas A Marston, Thomas Meitinger, Braxton D Mitchell, Felipe A Montellano, Takayuki Morisaki, Thomas H Mosley, Mike A Nalls, Børge G Nordestgaard, Martin J O'Donnell, Yukinori Okada, N Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M Psaty, Stephen S Rich, Jonathan Rosand, Marc S Sabatine, Ralph L Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L Satizabal, Carsten O Schmidt, Atsushi Shimizu, Nicholas L Smith, Kelly L Sloane, Yoichi Sutoh, Yan V Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P Torres-Aguila, Hemant K Tiwari, David-Alexandre Trégouët, Stella Trompet, Anil Man Tuladhar, Anne Tybjærg-Hansen, Marion Van Vugt, Riina Vibo, Shefali S Verma, Kerri L Wiggins, Patrik Wennberg, Daniel Woo, Peter W F Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Compass Consortium, Invent Consortium, Dutch Parelsnoer Initiative (Psi) Cerebrovascular Disease Study Group, Estonian Biobank, Precise4q Consortium, Finngen Consortium, Ninds Stroke Genetics Network (Sign), Megastroke Consortium, Siren Consortium, China Kadoorie Biobank Collaborative Group, Va Million Veteran Program, International Stroke Genetics Consortium (Isgc), Biobank Japan, Charge Consortium, Gigastroke Consortium, Iona Y Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J Grabe, J Wouter Jukema, Ina L Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M M Howson, Marguerite R Irvin, Hieab Adams, Sylvia Wassertheil-Smoller, Kaare Christensen, Mohammad A Ikram, Tatjana Rundek, Bradford B Worrall, G Mark Lathrop, Moeen Riaz, Eleanor M Simonsick, Janika Kõrv, Paulo H C França, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik De Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte M Ruigrok, Peter Ulrich Heuschmann, W T Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M Damrauer, Daniel I Chasman, Jerome I Rotter, Christopher D Anderson, John-Anker Zwart, Teemu J Niiranen, Myriam Fornage, Yung-Po Liaw, Sudha Seshadri, Israel Fernández-Cadenas, Robin G Walters, Christian T Ruff, Mayowa O Owolabi, Jennifer E Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stephanie Debette

Faculty, Staff and Student Publications

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

Protein Profiling By Reverse Phase Protein Array (Rppa) In Classical Hairy Cell Leukemia (Hcl) And Hcl-Variant, Fieke W Hoff, Ti'ara L Griffen, Yihua Qiu, Steven M Kornblau

Faculty, Staff and Student Publications

Classical hairy cell leukemia (HCL-c) and HCL variant (HCL-v) are recognized as separate entities with HCL-v having significantly shorter overall survival. Proteomic studies, shown to be prognostic in various forms of leukemia, have not been performed in HCL. We performed reverse phase protein array-based protein profiling with 384 antibodies in HCL-c (

Contemporary Outcomes In Idh-Mutated Acute Myeloid Leukemia: The Impact Of Co-Occurring Npm1 Mutations And Venetoclax-Based Treatment, Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Ghayas Issa, Ken Furudate, Tomoyuki Tanaka, Sherry Pierce, Guilin Tang, Keyur P Patel, Jeffrey Medeiros, Hussein A Abbas, Fadi Haddad, Daniel Hammond, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Naveen Pemmaraju, Marina Konopleva, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia, Sanam Loghavi, Courtney D Dinardo

Faculty, Staff and Student Publications

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and …

Clinical Outcomes And Impact Of Therapeutic Intervention In Patients With Acute Myeloid Leukemia Who Experience Measurable Residual Disease (Mrd) Recurrence Following Mrd-Negative Remission, Nicholas J Short, Walid Macaron, Tapan Kadia, Courtney Dinardo, Ghayas C Issa, Naval Daver, Sa Wang, Jeff Jorgensen, Daniel Nguyen, Aram Bidikian, Keyur P Patel, Sanam Loghavi, Marina Konopleva, Musa Yilmaz, Elias Jabbour, Abhishek Maiti, Hussein A Abbas, Elizabeth Shpall, Uday Popat, Gheath Al-Atrash, Sherry Pierce, Hagop M Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Recurrence of MRD in AML is associated with imminent relapse unless intervened upon. Change in chemotherapy regimen and/or immediate transplant improve outcomes.

B-Lymphoblastic Leukemia With Burkitt-Like Morphology And Aberrant Myeloperoxidase Expression: A Diagnostic Conundrum, Karen A Nahmod, Wei Wang, Karan Saluja, Zhenya Tang, L Jeffrey Medeiros, Beenu Thakral

Faculty, Staff and Student Publications

No abstract provided.

Clinical And Molecular Features Of Pediatric Cancer Patients With Lynch Syndrome, Sarah Scollon, Mohammad K Eldomery, Jacquelyn Reuther, Frank Y Lin, Samara L Potter, Lauren Desrosiers, Kenneth L Mcclain, Valeria Smith, Jack Meng-Fen Su, Rajkumar Venkatramani, Jianhong Hu, Viktoriya Korchina, Neda Zarrin-Khameh, Richard A Gibbs, Donna M Muzny, Christine Eng, Angshumoy Roy, D Williams Parsons, Sharon E Plon

Faculty, Staff and Students Publications

BACKGROUND: The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD).

PROCEDURE: We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies.

RESULTS: There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second …