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Lineage Deconvolution Using Chromatin Accessibility and DNA Methylation Shows a Spectrum of Lineage Characteristics and Differentiation States across Acute leukemias

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BLOOD 2017年第Sup1期130卷 1208-1208页

作者： Glass, Jacob L. Palia, Alyson J. Garrett-Bakelman, Francine E. Koche, Richard Levine, Ross L. Tallman, Martin S. Dillon, Richard James Grimwade, David Ferrando, Adolfo A. Valk, Peter J. M. Delwel, Ruud Figueroa, Maria E. Melnick, Ari Elemento, Olivier Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY Kenyon College Gambier OH Department of Biochemistry and Molecular Genetics University of Virginia School of Medicine Charlottesville VA Department of Medicine University of Virginia School of Medicine Charlottesville Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Division of Hematologic Oncology Leukemia Service Memorial Sloan-Kettering Cancer Center New York NY Kings College London London GBR King's College London London United Kingdom Institute for Cancer Genetics Columbia University New York NY Department of Hematology Erasmus University Medical Center Rotterdam NLD Erasmus MC Rotterdam NLD Umiami Miller School of Medicine/Sylvester Comp. Cancer Ctr. Miami FL Division of Hematology/Oncology Weill Cornell Medical College New York NY Caryl and Israel Englander Institute for Precision Medicine HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell Medical College New York NY

Hematopoietic differentiation is characterized by the organized epigenetic reprogramming of hematopoietic stem cells to terminally differentiated cells. Acute leukemias represent a disruption of this process and are c...

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Author Correction: FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

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Nature communications 2022年第1期13卷 7920页

作者： Joshua I Warrick Wenhuo Hu Hironobu Yamashita Vonn Walter Lauren Shuman Jenna M Craig Lan L Gellert Mauro A A Castro A Gordon Robertson Fengshen Kuo Irina Ostrovnaya Judy Sarungbam Ying-Bei Chen Anuradha Gopalan Sahussapont J Sirintrapun Samson W Fine Satish K Tickoo Kwanghee Kim Jasmine Thomas Nagar Karan Sizhi Paul Gao Timothy N Clinton Andrew T Lenis Timothy A Chan Ziyu Chen Manisha Rao Travis J Hollman Yanyun Li Nicholas D Socci Shweta Chavan Agnes Viale Neeman Mohibullah Bernard H Bochner Eugene J Pietzak Min Yuen Teo Gopa Iyer Jonathan E Rosenberg Dean F Bajorin Matthew Kaag Suzanne B Merrill Monika Joshi Rosalyn Adam John A Taylor Peter E Clark Jay D Raman Victor E Reuter Yu Chen Samuel A Funt David B Solit David J DeGraff Hikmat A Al-Ahmadie Department of Pathology and Laboratory Medicine Pennsylvania State University College of Medicine Hershey PA USA. Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA. Department of Urology Pennsylvania State University College of Medicine Hershey PA USA. Department of Public Health Sciences Pennsylvania State University College of Medicine Hershey PA USA. Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN USA. Bioinformatics and Systems Biology Laboratory Federal University of Parana Curitiba Paraná Brazil. BC Cancer Canada's Michael Smith Genome Sciences Centre Vancouver BC Canada. Urology Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA. Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA. Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Marie-Josée and Henry R. Kravis Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY USA. Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Department of Medicine Division of Hematology-Oncology Penn State Cancer Institute Hershey PA USA. Department of Urology Boston Children's Hospital Boston MA USA. Department of Urology University of Kansas Medical Center Kansas City MO USA. Levine Cancer Institute Atrium Health Charlotte NC USA. Department of Pathology and Laboratory Medicine Pennsylvania State University College of Medicine Hershey PA USA. ddegraff@pennstatehealth.psu.edu. Department of Urology Pennsylvania State University College of Medicine Hershey PA USA. ddegraff@pennstatehealth.psu.edu. Deparment of Biochemistry and Molecular Biology Pennsylvania State University College of Medicine Hershey PA USA. ddegraff@pennstatehealth.psu.edu. Department of Epidemiology and Biostatistics Memorial Sloan Kettering Ca

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SETBP1 and NRAS Mutations Are Frequent Events in Post-Myeloproliferative Neoplasm Acute Myeloid leukemia (post-MPN AML) Lacking JAK-STAT Activating Mutations

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BLOOD 2017年第Sup1期130卷 203-203页

作者： Menghrajani, Kamal Rapaport, Franck McNamara, Caroline Jane Devlin, Sean M. Famulare, Christopher Patel, Minal Medina, Juan Sandy, Lonette Kosiorek, Heidi Weinberg, Rona Singer Arruda, Andrea Schulman, Jessica Manshouri, Taghi Kremyanskaya, Marina Mascarenhas, John Hoffman, Ronald Gupta, Vikas Verstovsek, Srdan Levine, Ross L. Rampal, Raajit K. Memorial Sloan Kettering Cancer Center New York NY The Princess Margaret Cancer Center Toronto CAN Department of Biostatistics and Epidemiology Memorial Sloan Kettering Cancer Center New York NY Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY Mayo Clinic Phoenix AZ New York Blood Center New York NY University of Toronto Princess Margaret Cancer Centre Toronto Canada Department of Leukemia The University of Texas MD Anderson Cancer Center Houston TX Division of Hematology/Medical Oncology The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY Division of Hematology/Medical Oncology The Tisch Cancer Institute Mount Sinai School of Medicine New York NY Princess Margaret Cancer Centre Toronto Canada Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Background: The BCR/ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by JAK-STAT activating mutations (mutations...

Background: The BCR/ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by JAK-STAT activating mutations (mutations in JAK2, CALR, and MPL) . Approximately 10% of MPN patients in chronic phase are “triple-negative” for mutations in any of the three genes. Leukemic transformation (LT) of chronic-phase MPNs carries a poor prognosis, and the biologic and genetic mechanisms underlying transformation are poorly understood. Further, although no standard therapeutic approach to LT exists, conventional anti-leukemic therapies such as induction chemotherapy and the use of hypomethylating agents have been utilized. However, there is a paucity of data comparing these approaches, as well as evaluating the impact of genomic alterations on treatment outcomes. We have sought to address these issues through detailed analysis of a well-annotated multi-center cohort of post-MPN AML patients. Methods: Next-generation sequencing was performed on 114 patients at the time of LT. Sequencing of the entire coding sequence of 585 cancer-associated genes on 84 samples collected from Memorial Sloan Kettering Cancer Center, Princess Margaret Cancer Centre, and the Myeloproliferative Diseases Research Consortium (MPD-RC) was performed. Mutational calls were made in comparison to curated matched normals. Tumor-only mutational data was obtained from an additional 30 patients sequenced using the Foundation One Heme platform. Results: Of the 114 patients analyzed, 66 (58%) had a JAK2 mutation, 8 (7%) had a MPL mutation, and 9 (8%) had a CALR mutation (Figure 1). 32 patients (28%) had TN disease. Notably, SETBP1 and NRAS mutations occurred exclusively in the TN cohort, each occurring at a frequency of 18.8% (6/32). TP53 mutations were identified in 18.8% (6/32) of TN cases and 24% (20/82) of cases with JAK-STAT mutations. ASXL1 mutations occurred frequently in both the TN cohort and the JAK-STAT muta

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Synergistic Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms

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BLOOD 2016年第22期128卷 634-634页

作者： Rampal, Raajit K. Maria, Pinzon-Ortiz Varshini, Hanasoge Somasundara Amritha Levine, Ross L. Cao, Alex Leukemia Service Department of Medicine Memorial Sloan-Kettering Cancer Center New York NY Novartis Institutes for Biomedical Research Cambridge MA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Novartis Institutes for Biomedical Research/(currently: Bristol-Myers Squibb) Cambridge MA

Ruxolitinib has demonstrated significant benefits for patients with MPNs, including reduction of splenomegaly and improvement in symptom burden. However, ruxolitinib has limited ability to alter the natural history an...

Ruxolitinib has demonstrated significant benefits for patients with MPNs, including reduction of splenomegaly and improvement in symptom burden. However, ruxolitinib has limited ability to alter the natural history and biology of disease in MPNs. Furthermore, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise combinatorial treatment strategies to improve and extend the benefits of ruxolitinib therapy. Activation of the JAK-STAT pathway is a hallmark of MPN disease biology. JAK2 signaling is also known to engage other downstream pathways, which may expose novel therapeutic vulnerabilities. For example, JAK2 V617Fhas been demonstrated to increase CDC25A transcription and down-regulate p27 expression via STAT5 activation, which has been postulated to trigger the activation of cyclin dependent kinases such as CDK4. Additionally, activated STATs and PIM kinases have been shown to activate D cyclins that are upstream of CDK4/6. These observations have led us to investigate the hypothesis that CDK4/6 inhibition, in conjunction with JAK1/2 and PIM kinase inhibition, may results in synergistic therapeutic efficacy. Using INC424 (JAK1/2 inhibitor ruxolitinib), PIM447 (pan-PIM inhibitor), and LEE011 (CDK4/6 inhibitor) we first sought to determine the effect of combination therapy with INC424 and PIM447 or INC424 and LEE011 compared with monotherapy in allografted Ba/f3 cells expressing EPOR-JAK2 V617F. In comparison to treatment with single agents, the combination of INC424 and LEE011 demonstrated synergistic anti-tumor activity. Subsequent evaluation of the triple combination of INC424, PIM447 and LEE011 demonstrated further enhancement of reduction in whole-body tumor burden, spleen size and a marked reduction in JAK2 mutant allele burden. We next sought to evaluate this triple-therapy strategy in a MPL W515L-mediated murine retroviral transplant model which most close

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Clonal Heterogeneity in Differentiation Response and Resistance to the IDH2 Inhibitor Enasidenib in Acute Myeloid leukemia

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BLOOD 2017年第Sup1期130卷 724-724页

作者： Quek, Lynn David, Muriel Kennedy, Alison Metzner, Marlen Amatangelo, Michael Shih, Alan H. Stoilova, Bilyana Karamitros, Dimitris Quivoron, Cyril Heiblig, Mael Willekens, Christophe Saada, Veronique Peniket, Andrew Bernard, Olivier Agresta, Sam Yen, Katharine Stein, Eytan M. De Botton, Stephane Thakurta, Anjan Levine, Ross L. Penard-Lacronique, Virginie Vyas, Paresh Department of Clinical Haematology Oxford University Hospitals NHS Foundation Trust Oxford United Kingdom MRC Weatherall Institute of Molecular Medicine University of Oxford Oxford United Kingdom Gustave Roussy INSERM U1170 Université Paris-Saclay Villejuif France Celgene Corporation Summit NJ Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Department of Hematology Gustave Roussy Cancer Center Villejuif France Département de Biologie-Pathologie Gustave Roussy Université Paris-Saclay Villejuif France Gustave Roussy INSERM U1170 Université Paris-Saclay Villejuif France Agios Pharmaceuticals Inc. Cambridge MA Division of Hematologic Oncology Leukemia Service Memorial Sloan Kettering Cancer Center New York NY Gustave Roussy Département d'hématologie et Département d'innovation Thérapeutique F-94805 Villejuif France Université Paris-Saclay Gustave Roussy INSERM U1170 Villejuif France Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Background Mutations in Isocitrate Dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid leukemia (AML). In preclinical models mutant IDH2 (mIDH2) causes partial hemopoietic differentiation block1. Rece...

Background Mutations in Isocitrate Dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid leukemia (AML). In preclinical models mutant IDH2 (mIDH2) causes partial hemopoietic differentiation block1. Recently, we showed that single agent enasidenib, a first-in-class, selective mIDH2 inhibitor, produces a 40% response in relapsed/refractory AML patients by promoting differentiation2. Here, we studied response and acquired resistance to enasidenib, in sequential samples treated in the Phase 1 study of Enasidenib in relapsed/ refractory AML patients. Results We studied a cytogenetically and genetically representative subset of 25 patients enriched for enasidenib responders, genotyped by whole exome sequencing (WES) or cancer gene panel targeted re-sequencing. Pre-enasidenib, differentiation arrest in these AML patients resulted in abnormally expanded leukaemic progenitors or precursors and diminished mature haematopoietic populations. Complete remission (CR) post-enasidenib was associated with in increased mature populations, near-normalisation of haematopoietic progenitor profiles, and restoration of in vitro progenitor function. In most patients, mature blood cells (of erythroid and granulocyte-monocyte lineages) post-enasidenib are IDH2 mutant, consistent with enasidenib inducing differentiation of IDH2 mutant leukaemic progenitors/ precursors. Each mIDH2 patient studied had on average 13 somatic, non-synonymous exonic or splice site mutations in addition to IDH2 . We used single cell genotyping (SCG) to reveal linear or branching clonal structures in mIDH2 AML. We combined clonal structure data and immunophenotyping of haematopoietic progenitor, precursor and mature populations to track functional behaviour of mIDH2 clones before, and during enasidenib treatment. We demonstrate, for the first time, that mIDH2 subclones within the same patient are functionally heterogeneous: both in their ability to differentiate pre-enasidenib, and in their sensitivity

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Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone-Marrow Transplantation in Mice

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BLOOD 2017年第Sup1期130卷 1899-1899页

作者： Staffas, Anna da Silva, Marina Burgos Slingerland, Ann E. Lazrak, Amina Shono, Yusuke Durham, Benjamin H. Stein-Thoeringer, Christoph K. Docampo, Melissa Jay, Hillary V. Lieberman, Sophia R. Smith, Odette M. Pamer, Eric G. Peled, Jonathan U. Jenq, Robert R. van den Brink, Marcel R. M. Department of Immunology Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Memorial Sloan Kettering Cancer Center New York NY Weill Medical College of Cornell University New York NY Infectious Disease Service Lucille Castori Center for Microbes Inflammation and Cancer Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Departments of Genomic Medicine and Stem Cell Transplantation Cellular Therapy Division of Cancer Medicine University of Texas MD Anderson Cancer Center Houston TX Adult Bone Marrow Transplant Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Bone-marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Delayed immune recon...

Bone-marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Delayed immune reconstitution is an important contributor to transplant-related morbidity and mortality (Maury et al., Br J Haematol, 2001; Small et al., Blood, 1999). Thus, understanding the mechanisms by which the immune system reconstitutes and how environmental exposures might influence this process is an important objective in improving outcomes after BMT. The intestinal microbiota shapes both mucosal and systemic immunity and contributes to steady-state hematopoiesis (Belkaid and Hand, Cell, 2014). To determine the role of the intestinal flora in hematopoietic reconstitution following BMT, we performed syngeneic BMT after lethal irradiation in mice with an intact intestinal flora (control, C/No abx) and in mice treated with two different antibiotic (abx) regimens administered in the drinking water: ampicillin + enrofloxacin (AmpEnro/AE) or vancomycin + amikacin (VancAmik/VA). While both regimens depleted the intestinal flora 1000-fold, ampicillin and enrofloxacin are both relatively well absorbed in the intestine while vancomycin and amikacin both have poor oral bioavailability with negligible systemic effects. BMT recipients treated with either of the abx regimens had lower white blood cell (WBC) counts and, in particular, lower lymphocyte counts compared to untreated BMT recipients (Fig 1A). Fecal microbiota transfer (FMT) with an abx-resistant intestinal flora (Caballero et al., Cell Host Microbe, 2017) rescued the impaired hematopoietic reconstitution in AE-treated mice (Fig 1B). These data rule out a direct inhibitory effect of abx on hematopoietic recovery. When we examined multiple compartments of the hematopoietic cascade we observed that flora depletion significantly impaired hematopoiesis specifically in the lymphoid and myeloid compartments of the bone mar

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Activation of JAK/STAT Signaling in Megakaryocytes Is Necessary and Sufficient for Myeloproliferation In Vivo

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BLOOD 2016年第22期128卷 949-949页

作者： Wen, Q. Jeremy Woods, Brittany Yang, Qiong Sophia, Chiu Lillu, Gu Rapaport, Franck Levine, Ross L. Crispino, John Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Northwestern University Division of Hematology and Oncology Chicago IL Louis V. Gerstner Sloan Kettering Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY Division of hematology and oncology Northwestern University chicago Human Oncology and Pathogenesis Program Memorial Sloan-Kettering Cancer Center new york Leukemia Center Memorial Sloan Kettering Cancer Center New York City NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY Memorial Sloan-Kettering Cancer Center New York NY Medicine Hematology/Oncology Northwestern University Chicago IL

Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPN). It is has been long known that abnormal megakaryocytes secrete elevated levels of cytokines such as TGFβ , resulting in pathologies i...

Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPN). It is has been long known that abnormal megakaryocytes secrete elevated levels of cytokines such as TGFβ , resulting in pathologies including bone marrow fibrosis. Two recent studies showed that megakaryocytes regulate the quiescence of HSCs, raising the possibility that megakaryocytes may promote the MPNs by influencing the biology of non-malignant HSCs. However, the mechanism by which megakaryocytes regulate the initiation and progression of MPNs is largely unknown. To study the role of megakaryocytes in the MPNs, we analyzed the phenotype of PF4-Cre/Jak2V617F mice in which Jak2 is expressed in the megakaryocyte lineage from the endogenous locus, in contrast to previous studies, which used transgenic models. Selective activation of Jak2V617F was confirmed by allele-specific qPCR. CD41+ cells were positive for mutant Jak2 , whereas sorted stem/progenitor cells and erythroid cells were Jak2 wild-type. Furthermore, flow cytometry showed that Stat5 activation was present in megakaryocytes, but not in erythroid or myeloid cells. Activation of JAK-STAT signaling caused an expansion of megakaryocytes in the bone marrow and spleen and a modest increase in the platelet count. Surprisingly, PF4-Cre/Jak2V617F mice also displayed a robust expansion of TER119( low) /CD71(high) and TER119 ( high ) /CD71 ( high ) red cells in the spleen, increased hematocrit and splenomegaly. Histological examination of the spleen revealed expansion of the erythroid lineage coupled with disrupted splenic architecture and fibrosis. This PV-like phenotype was fully penetrant and comparable to that of Vav-Cre/Jak2V617F mice, which express mutant Jak2 in all hematopoietic lineages. Profiling of hematopoietic progenitors by flow cytometry demonstrated that myeloid progenitor populations were expanded and skewed toward the erythroid-megakaryocyte lineage with a significant increase in Pre Meg-E, Pre CFU-E and MKPs in th

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Bone Marrow-Based and Longitudinal Blood-Based MRD Tracking in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (DKRd): A Correlative and Clinical Phase II Study

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Blood 2018年 132卷 3281-3281页

作者： Ola Landgren Katie Thoren Malin Hultcrantz Alexander M. Lesokhin Nikoletta Lendvai Sham Mailankody Eric L. Smith Hani Hassoun Sydney X. Lu Donna Mastey Meghan Salcedo Victoria Diab Allison Sams Dennis Verducci Katie Jones Angela Harrison Even H Rustad Venkata Yellapantula Theresia Akhlaghi Heather J. Landau Neha Korde Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Adult Bone Marrow Transplant Service Department of Medicine Memorial Sloan Kettering Cancer Center Scarsdale NY

INTRODUCTION Using Carfilzomib, Lenalidomide and Dexamethasone (KRd) combination therapy in newly diagnosed multiple myeloma patients lead to ~40% minimal residual disease (MRD) negativity rate. Here, we use KRd in co...

INTRODUCTION Using Carfilzomib, Lenalidomide and Dexamethasone (KRd) combination therapy in newly diagnosed multiple myeloma patients lead to ~40% minimal residual disease (MRD) negativity rate. Here, we use KRd in combination with daratumumab (DKRd); and treatment response is assessed with extensive correlative science including parallel bone-marrow-based and blood-based MRD tracking, together with targeted DNA sequencing of baseline bone marrow samples. Primary end-point is to rule out 60% and to target up to 80% MRD negativity rate. METHODS This is a single-arm, Phase II clinical trial based on Simon's optimal two-stage design. The first cohort (twice-a-week carfilzomib) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The second cohort (once-a-week carfilzomib) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the first cohort. For fit patients, stemcell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone-marrow-based (10-color single tube flowcytometry, invivoscribe V(D)J sequencing) as well as blood-based (MALDI-TOF and QTOF-mass spectrometry [MS]) for MRD tracking. Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). Here, we present the first stage (N=28) of the first cohort (twice-a-week carfilzomib). We are waiting for the results to mature before the second stage (N=13) of the first cohort can open. The second cohort (once-a-week carfilzo

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PHF6 Mutations Are Mutually Exclusive to TP53 Mutations, and Define a Distinct Subgroup of Secondary Acute Myeloid leukemia Associated with a Primitive Stem/Progenitor Immunophenotype, Absent Complex Karyotype and Relatively Better Outcomes

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Blood 2018年 132卷 2788-2788页

作者： Wenbin Xiao Aaron D Goldberg Brian Ball Christopher Famulare Friederike Pastore Martin S. Tallman Yanming Zhang Maria E Arcila Elli Papaemmanuil Ross L. Levine Mikhail Roshal Hematopathology Diagnostic Service Department of Pathology Memorial Sloan Kettering New York NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Leukemia service Memorial Sloan Kettering Cancer Center NEW YORK NY MSKCC HOPP Lab Prof. RL Levine New York NY Leukemia Service Department of Medicine Memorial Sloan-Kettering Cancer Center New York NY Department of Pathology Memorial Sloan Kettering Cancer Center New York NY Department of Pathology and Department of Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY

Introduction Secondary acute myeloid leukemia (s-AML) includes AML with myelodysplasia-related changes (AML-MRC) transformed from an antecedent diagnosis of myelodysplastic syndrome (MDS) or from myeloproliferative an...

Introduction Secondary acute myeloid leukemia (s-AML) includes AML with myelodysplasia-related changes (AML-MRC) transformed from an antecedent diagnosis of myelodysplastic syndrome (MDS) or from myeloproliferative and myelodysplastic overlap syndrome (MPN/MDS), as well as therapy-related AML (t-AML) arising in patients with prior exposure to leukemogenic therapies. S-AML has a dismal prognosis. Although the genomic profiling of AML has been well studied, few studies have focused on the molecular aberrations of s-AML. A recent study has demonstrated shared genomic aberrations by AML-MRC and t-AML including mutations in TP53, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 . Another recent study has shown that AML patients with mutations in TP53 and chromatin-splicesosome confer poor prognosis and likely represent s-AML. As such, further characterization of the genomic landscape of s-AML is needed. Recurrent somatic PHF6 mutations are rare in de novo AML (~3%), but the frequency and characteristics of PHF6 mutated s-AML are largely unknown. Patients and Methods AML-MRC and t-AML patients were searched from the patient database at the MSKCC between 1/2014 and 12/2016. All the patients were reviewed and the diagnosis was confirmed. Only patients with genomic sequencing studies (a targeted NGS panel comprising 30 genes with mutations enriched in AML) performed at diagnosis were included. Results 152 patients were identified. There were 7 t-AML patients with favorable cytogenetic abnormalities that likely represent a distinct biological subgroup; therefore these cases were excluded from further analysis. AML-MRC (N=75) and t-AML (N=70) patients had similar clinical characteristics including ages, gender distribution, cytogenetic risk, treatment and survival (median survival: 8 months in t-AML and 10 months in AML-MRC, p=0.4); The mutational profiles of AML-MRC and t-AML cohorts were also comparable with recurrent TP53, PHF6, RAS, and RUNX1 mutations, albeit with

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The Mutational Landscape and Immune Microenvironment of Primary Intestinal Follicular Lymphoma (PIFL)

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BLOOD 2017年第Sup1期130卷 2735-2735页

作者： Hellmuth, Johannes Louissaint, Abner Szczepanowski, Monika Habe, Sarah Pastore, Alessandro Staiger, Annette M. Hartmann, Sylvia Kridel, Robert Ducar, Matthew D. Koch, Peter Dreyling, Martin Hansmann, Martin-Leo Ott, German Rosenwald, Andreas Gascoyne, Randy D. Weinstock, David M. Hiddemann, Wolfgang Klapper, Wolfram Weigert, Oliver Department of Medicine Division of Hematology & Medical Oncology Weill Cornell Medicine New York Department of Medicine III University Hospital LMU Brooklyn NY Massachusetts General Hospital Boston MA Department of Pathology Hematopathology Section and Lymph Node Registry University of Kiel Kiel Germany Experimental Leukemia and Lymphoma Research (ELLF) University Hospital LMU Munich Germany Department of Medicine III University Hospital LMU Munich Germany Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Department of Clinical Pathology Robert-Bosch-Krankenhaus Stuttgart Germany Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart and University of Tuebingen Stuttgart Germany Institute of Pathology University Hospital of Frankfurt Frankfurt am Main Germany Princess Margaret Cancer Centre Toronto Canada Center for Cancer Genome Discovery Dana-Farber Cancer Institute Boston MA University Hospital Muenster Department of Medicine A Muenster Germany Department of Clinical Pathology Robert Bosch Hospital Stuttgart Germany Institute of Pathology University of Wuerzburg Wuerzburg Germany Centre for Lymphoid Cancer British Columbia Cancer Agency Vancouver Canada Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Department of Medicine III University Hospital LMU Munich Munich Germany Experimental Leukemia and Lymphoma Research (ELLF) University Hospital LMU Munich Munich Germany German Cancer Research Center (DKFZ) Heidelberg Germany

Introduction: Follicular lymphoma (FL) comprises a heterogeneous group of diseases. Typical FL (TFL) most commonly presents with advanced stage (AS), has a variable clinical course, and is incurable. A small subset of...

Introduction: Follicular lymphoma (FL) comprises a heterogeneous group of diseases. Typical FL (TFL) most commonly presents with advanced stage (AS), has a variable clinical course, and is incurable. A small subset of TFL cases present with limited stage (LS) disease, and may be cured with radiotherapy. Primary cutaneous follicular lymphoma and pediatric-type follicular lymphoma (PTFL) are non-typical FL subtypes with localized presentation and invariably benign behavior. In contrast to ASTFL, these subtypes lack BCL2 -rearrangements. We recently discovered that, in contrast to typical FLs, the majority of PTFL cases are driven by mutations activating the MAP kinase pathway and lack mutations in epigenetic modifier genes (Louissaint, Blood 2016; Schmidt, Blood 2017). Primary intestinal FL (PIFL) is another non-typical variant of FL, characterized by its distinctive restriction to the intestine (most commonly the duodenum). Despite this striking behavior, PIFL is indistinguishable from ASTFL and LSTFL by routine histology and immunohistochemistry (IHC) alone, and has a remarkably low tendency to progress or disseminate. The cell-intrinsic alterations (e.g. mutations) and cell-extrinsic factors (microenvironment) underlying the distinctive clinical behavior of PIFL are unknown. Patients and Methods: A total of 38 PIFL cases were available through the Kiel Lymph Node Registry and the Dana-Farber Cancer Institute (DFCI) / Massachusetts General Hospital (MGH), with clinical follow-up for 19 cases. We excluded cases of intestinal FL with evidence of mesenteric lymph node involvement or extra-intestinal manifestation. A total of 17 LSTFL cases were available from DFCI / MGH. We used 241 ASTFL cases from our previous study (Pastore, Lancet oncology 2015) as a reference *** targeted mutational landscape was determined by customized hybrid-capture targeted sequencing of 104 genes. In addition, we performed whole-exome-sequencing (WES) on 11 PIFL. The FL immune microenv

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