Publications by authors named "Aaron D Goldberg"

26 Publications

  • Page 1 of 1

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.

Blood Adv 2021 Mar;5(5):1552-1564

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
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http://dx.doi.org/10.1182/bloodadvances.2020003734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948282PMC
March 2021

Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub.

Blood Adv 2020 12;4(23):5966-5975

Division of Hematology/Oncology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada.

Coronavirus disease 2019 (COVID-19) is an illness resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019. Patients with cancer, and especially those with hematologic malignancies, may be at especially high risk of adverse outcomes, including mortality resulting from COVID-19 infection. The ASH Research Collaborative COVID-19 Registry for Hematology was developed to study features and outcomes of COVID-19 infection in patients with underlying blood disorders, such as hematologic malignancies. At the time of this report, data from 250 patients with blood cancers from 74 sites around the world had been entered into the registry. The most commonly represented malignancies were acute leukemia (33%), non-Hodgkin lymphoma (27%), and myeloma or amyloidosis (16%). Patients presented with a myriad of symptoms, most frequently fever (73%), cough (67%), dyspnea (50%), and fatigue (40%). Use of COVID-19-directed therapies, such as hydroxychloroquine (n = 76) or azithromycin (n = 59), was common. Overall mortality was 28%. Patients with a physician-estimated prognosis from the underlying hematologic malignancy of <12 months at the time of COVID-19 diagnosis and those with relapsed/refractory disease experienced a higher proportion of moderate/severe COVID-19 disease and death. In some instances, death occurred after a decision was made to forgo intensive care unit admission in favor of a palliative approach. Taken together, these data support the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection. Batch submissions from sites with high incidence of COVID-19 infection are planned to support future analyses.
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http://dx.doi.org/10.1182/bloodadvances.2020003170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724912PMC
December 2020

Single-cell mutation analysis of clonal evolution in myeloid malignancies.

Nature 2020 11 28;587(7834):477-482. Epub 2020 Oct 28.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
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http://dx.doi.org/10.1038/s41586-020-2864-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677169PMC
November 2020

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1-mutated acute myeloid leukemia.

Blood 2021 Mar;137(10):1377-1391

Human Oncology and Pathogenesis Program, Molecular Cancer Medicine Service.

Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in ∼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
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http://dx.doi.org/10.1182/blood.2020007897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955409PMC
March 2021

Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.

Cancer Discov 2020 Oct 30;10(10):1500-1513. Epub 2020 Jun 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1 leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant acute myeloid leukemia. SIGNIFICANCE: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584353PMC
October 2020

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

Lancet Haematol 2020 Aug 18;7(8):e601-e612. Epub 2020 Jun 18.

Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.
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http://dx.doi.org/10.1016/S2352-3026(20)30205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302757PMC
August 2020

Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study.

Leuk Res 2020 08 7;95:106385. Epub 2020 Jun 7.

Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.

There is a significant need for improved therapeutics in older patients with acute leukemia. Camidanlumab tesirine is an antibody-drug conjugate against CD25, an antigen expressed in several malignancies, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This open-label, dose-escalation and -expansion study (NCT02588092) assessed the safety, activity, pharmacokinetics (PK), and immunogenicity of camidanlumab tesirine in patients with relapsed/refractory ALL/AML. A total of 35 patients (34 AML and 1 ALL) were enrolled and received camidanlumab tesirine intravenously at 3-92 μg/kg once every three weeks (Q3W, n = 26) or 30 or 37.5 μg/kg every week (QW, n = 9). One dose-limiting toxicity of maculopapular rash occurred in the 30 μg/kg QW group; the maximum tolerated dose was not reached. No additional safety concerns or adverse events (AEs) of interest were identified. The most common (>10 % of patients) Grade ≥3 treatment-emergent AEs were febrile neutropenia (25.7 %), lymphopenia, neutropenia, thrombocytopenia or fatigue (all 14.3 %), pneumonia, increased gamma-glutamyltransferase, and hypophosphatemia (each 11.4 %). No signal for serious immune-related AEs such as Guillain-Barré syndrome/polyradiculopathy was observed and there was no evidence of immunogenicity. PK showed rapid clearance with apparent half-life <2 days for conjugated and total antibody, suggesting that Q3W dosing may be insufficient for therapeutic efficacy, and prompting exploration of a QW schedule. Two patients achieved complete responses with incomplete hematologic recovery; one each at 30 and 37.5 μg/kg QW. The trial was terminated during dose escalation due to programmatic reasons other than safety. Hence, recommended dose was not determined.
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http://dx.doi.org/10.1016/j.leukres.2020.106385DOI Listing
August 2020

Comparison of induction strategies and responses for acute myeloid leukemia patients after resistance to hypomethylating agents for antecedent myeloid malignancy.

Leuk Res 2020 06 1;93:106367. Epub 2020 May 1.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States.

Outcomes in patients with secondary acute myeloid leukemia (sAML) (including therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC)) are poor. Patients treated with hypomethylating agents (HMAs) for antecedent hematological malignancy (AHM) have suboptimal responses to induction chemotherapy upon transformation to AML. We investigated outcomes after various induction strategies in patients with sAML who had prior HMA exposure. We identified 242 patients with sAML who had prior HMA treatment for AHM and later received induction chemotherapy upon AML transformation and divided into 3 cohorts based on induction regimen: (A) CLAG/M (B) 7 + 3 and (C) CPX-351. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.2% in cohort C (p = 0.005 between cohort A and B) (p = 0.329 between cohorts A and C) (p = 0.402 between cohorts B and C). The early death rates were not significantly different among the three cohorts (p = 0.200). In patients who received ≤4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) with a trend toward better overall survival (OS) (19.9 vs. 5.5 months) compared to >4 cycles (p = 0.092). There was no significant difference in median OS among the 3 groups: cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p = 0.887). We demonstrate that CLAG/M and CPX-351 yield higher CR/CRi rates compared to 7 + 3 in patients with sAML after HMA failure. Median OS remains poor and did not differ among the 3 groups, illustrating the unmet need for more efficacious therapy for sAML patients following HMA failure.
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http://dx.doi.org/10.1016/j.leukres.2020.106367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771257PMC
June 2020

Leukemia stem cell gene expression signatures contribute to acute myeloid leukemia risk stratification.

Haematologica 2020 03;105(3):533-536

Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.3324/haematol.2019.241117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049345PMC
March 2020

Immunotherapy for acute myeloid leukemia: from allogeneic stem cell transplant to novel therapeutics.

Leuk Lymphoma 2019 12 23;60(14):3350-3362. Epub 2019 Jul 23.

Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Immunotherapy in the form of allogeneic stem cell transplantation (SCT) plays an instrumental role in the treatment of acute myeloid leukemia (AML), with non-transplant modalities of immunotherapy including checkpoint blockade now being actively explored. Here, we provide an overview of the graft versus leukemia (GVL) effect in AML as a window into understanding the prospects of AML immunotherapy. We explore the roles of various cell types in orchestrating anti-leukemic immunity, as well as those contributing to the unique immune suppressive state of myeloid diseases. We discuss specific approaches to engage the immune system, while noting the challenges of the AML antigen landscape and the barriers to immune modulation. We review the potential for immunomodulatory agents in combination with cellular therapies, donor lymphocyte infusion, and following SCT. Finally, to address the challenge of minimal residual disease (MRD) following chemotherapy, we propose combination epigenetic and immunotherapy for the eradication of MRD.
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http://dx.doi.org/10.1080/10428194.2019.1639167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928392PMC
December 2019

BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

Cancer Immunol Res 2019 07 21;7(7):1047-1053. Epub 2019 May 21.

Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices ( ), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline ( = 0.89-0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs ( = 0.56-0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606365PMC
July 2019

Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: Novel Combinations and Therapeutic Targets.

Curr Oncol Rep 2019 03 23;21(4):37. Epub 2019 Mar 23.

Department of Medicine, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose Of Review: Immune checkpoint therapy has dramatically changed the therapeutic landscape of solid malignancies. Here, we review the scientific rationale and current data evaluating immune checkpoint inhibitors in acute myeloid leukemia (AML).

Recent Findings: Immune checkpoint inhibitor monotherapy has shown limited clinical activity in AML. Initial results from early-phase clinical trials suggest that rational combinations of immune checkpoint inhibition with hypomethylating agents (HMAs) are safe and potentially more promising. There are currently no data directly comparing immune checkpoint inhibition to standard therapies. Emerging immune targets more specific for leukemia cells including LILRB4 may improve future therapeutic efficacy. The success of immune checkpoint inhibition in AML has been modest to date. However, an improved understanding of the biology and the use of rational combinations has potential to improve rates of durable responses. Multiple clinical trials in AML are currently evaluating the use of immune checkpoints alone and in combination.
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http://dx.doi.org/10.1007/s11912-019-0781-7DOI Listing
March 2019

Loss of plasmacytoid dendritic cell differentiation is highly predictive for post-induction measurable residual disease and inferior outcomes in acute myeloid leukemia.

Haematologica 2019 07 6;104(7):1378-1387. Epub 2018 Dec 6.

Department of Pathology, Hematopathology Diagnostic Service

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; =0.077) and 3.83 (95%CI: 1.51-9.74; =0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% 2 of 18, 11%; =0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML.
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http://dx.doi.org/10.3324/haematol.2018.203018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601104PMC
July 2019

Clinical Development of PD-1 Blockade in Hematologic Malignancies.

Cancer J 2018 Jan/Feb;24(1):31-35

From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway.
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http://dx.doi.org/10.1097/PPO.0000000000000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785103PMC
March 2019

Brain MRS glutamine as a biomarker to guide therapy of hyperammonemic coma.

Mol Genet Metab 2017 05 10;121(1):9-15. Epub 2017 Mar 10.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, VA Boston Healthcare System, Boston, MA 02115, USA. Electronic address:

Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N-carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate. Improvement in mental status mirrored brain glutamine levels, as coma persisted for 48h after plasma ammonia normalized. We hypothesize that the slower clearance for brain glutamine levels accounts for the delay in improvement following initiation of treatment in cases of chronic hyperammonemia. We propose MRS to monitor brain glutamine as a noninvasive approach to be utilized for diagnostic and therapeutic monitoring purposes in adult patients presenting with idiopathic hyperammonemia.
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http://dx.doi.org/10.1016/j.ymgme.2017.03.003DOI Listing
May 2017

Down for the count in acute myeloid leukemia.

Blood 2016 11;128(18):2195-2197

MEMORIAL SLOAN KETTERING CANCER CENTER.

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http://dx.doi.org/10.1182/blood-2016-09-738765DOI Listing
November 2016

Genome editing a mouse locus encoding a variant histone, H3.3B, to report on its expression in live animals.

Genesis 2014 Dec 6;52(12):959-66. Epub 2014 Oct 6.

Ansary Stem Cell Institute and Department of Medicine, Weill Cornell Medical College, New York, New York; Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York.

Chromatin remodeling via incorporation of histone variants plays a key role in the regulation of embryonic development. The histone variant H3.3 has been associated with a number of early events including formation of the paternal pronucleus upon fertilization. The small number of amino acid differences between H3.3 and its canonical counterparts (H3.1 and H3.2) has limited studies of the developmental significance of H3.3 deposition into chromatin due to difficulties in distinguishing the H3 isoforms. To this end, we used zinc-finger nuclease (ZFN) mediated gene editing to introduce a small C-terminal hemagglutinin (HA) tag to the endogenous H3.3B locus in mouse embryonic stem cells (ESCs), along with an internal ribosome entry site (IRES) and a separately translated fluorescent reporter of expression. This system will allow detection of expression driven by the reporter in cells, animals, and embryos, and will facilitate investigation of differential roles of paternal and maternal H3.3 protein during embryogenesis that would not be possible using variant-specific antibodies. Further, the ability to monitor endogenous H3.3 protein in various cell lineages will enhance our understanding of the dynamics of this histone variant over the course of development.
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http://dx.doi.org/10.1002/dvg.22827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844183PMC
December 2014

Tumors metastatic to the heart.

Circulation 2013 Oct;128(16):1790-4

Department of Medicine (A.D.G.), Noninvasive Cardiovascular Imaging Program, Department of Medicine (Cardiovascular Division) and Radiology (R.B.), and Department of Pathology (R.F.P.), Brigham and Women's Hospital, Boston, MA.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000790DOI Listing
October 2013

Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells.

Cell 2013 Sep;155(1):107-20

Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York, 10065 USA.

Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions enriched with the histone variant H3.3. Here, we show that, in mouse embryonic stem cells (ESCs), H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. Upon H3.3 depletion, these promoters show reduced nucleosome turnover measured by deposition of de novo synthesized histones and reduced PRC2 occupancy. Further, we show H3.3-dependent interaction of PRC2 with the histone chaperone, Hira, and that Hira localization to chromatin requires H3.3. Our data demonstrate the importance of H3.3 in maintaining a chromatin landscape in ESCs that is important for proper gene regulation during differentiation. Moreover, our findings support the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an "active" chromatin state.
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http://dx.doi.org/10.1016/j.cell.2013.08.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838450PMC
September 2013

Distinct factors control histone variant H3.3 localization at specific genomic regions.

Cell 2010 Mar;140(5):678-91

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc-finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells.
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http://dx.doi.org/10.1016/j.cell.2010.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885838PMC
March 2010

New functions for an old variant: no substitute for histone H3.3.

Curr Opin Genet Dev 2010 Apr 12;20(2):110-7. Epub 2010 Feb 12.

The Rockefeller University, New York, NY 10065, USA.

Histone proteins often come in different variants serving specialized functions in addition to their fundamental role in packaging DNA. The metazoan histone H3.3 has been most closely associated with active transcription. Its role in histone replacement at active genes and promoters is conserved to the single histone H3 in yeast. However, recent genetic studies in flies have challenged its importance as a mark of active chromatin, and revealed unexpected insights into essential functions of H3.3 in the germline. With strikingly little amino acid sequence difference to the canonical H3, H3.3 therefore accomplishes a surprising variety of cellular and developmental processes.
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http://dx.doi.org/10.1016/j.gde.2010.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860041PMC
April 2010

Epigenetics: a landscape takes shape.

Cell 2007 Feb;128(4):635-8

Laboratory of Chromatin Biology, The Rockefeller University, New York, NY 10021, USA.

Epigenetics has recently evolved from a collection of diverse phenomena to a defined and far-reaching field of study. In this Essay, we examine the epistemology of epigenetics, provide a brief overview of underlying molecular mechanisms, and suggest future challenges for the field.
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http://dx.doi.org/10.1016/j.cell.2007.02.006DOI Listing
February 2007

Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA).

Proc Natl Acad Sci U S A 2002 Dec 20;99(25):16081-6. Epub 2002 Nov 20.

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Steroid receptor RNA activator (SRA) is an RNA transcript that functions as a eukaryotic transcriptional coactivator for steroid hormone receptors. We report here the isolation and functional characterization of distinct RNA substructures within the SRA molecule that constitute its coactivation function. We used comparative sequence analysis and free energy calculations to systematically study SRA RNA subdomains for identification of structured regions and base pairings, and we used site-directed mutagenesis to assess their functional consequences. Together with genetic deletion analysis, this approach identified six RNA motifs in SRA important for coactivation. Because all nucleotide changes in the mutants that disrupted SRA function were silent mutations presumed not to alter deduced encoded amino acid sequence, our analysis provides strong evidence that SRA-mediated coactivation is executed by distinct RNA motifs and not by an encoded protein.
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http://dx.doi.org/10.1073/pnas.192571399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC138568PMC
December 2002