Publications by authors named "Andrew A Lane"

49 Publications

Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.

Blood 2021 May;137(18):2463-2480

Broad Institute of MIT and Harvard, Cambridge, MA.

Lineage plasticity and stemness have been invoked as causes of therapy resistance in cancer, because these flexible states allow cancer cells to dedifferentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) carrying activating NOTCH1 mutations via full-length single-cell RNA sequencing (scRNA-seq) of malignant and microenvironmental cells. We identified 2 highly distinct stem-like states that critically differed with regard to cell cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrated Notch activation and were effectively eliminated in patients by Notch inhibition, whereas slow-cycling stem-like cells were Notch independent and rather relied on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we found that both stem-like states could differentiate into a more mature leukemia state with prominent immunomodulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promoted an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that expressed HAVCR2, the cognate receptor for LGALS9. Our study identified complex interactions between signaling programs, cellular plasticity, and immune programs that characterize ETP-ALL, illustrating the multidimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem seem most promising to successfully eliminate tumor cells that escape treatment through coexisting transcriptional programs.
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http://dx.doi.org/10.1182/blood.2019004547DOI Listing
May 2021

Targeting CD123 in AML.

Authors:
Andrew A Lane

Clin Lymphoma Myeloma Leuk 2020 Sep;20 Suppl 1:S67-S68

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address:

An ideal cell surface target for therapy in leukemia would be: tumor-specific (not expressed on normal cells) or at least enriched on tumor cells, necessary for tumor but not for normal cell survival, internalized efficiently (if the surface-targeted agent is conjugated to chemotherapy or a toxin molecule), and recycled rapidly to the cell surface. While a single target that meets all of these criteria has not yet been discovered in AML, CD123 has emerged as an attractive candidate. The first-in-class CD123-targeting agent, tagraxofusp-erzs (SL-401) was approved in 2018 for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is currently in trials for several other hematologic malignancies, including AML. Several other CD123-targeted drugs are in development.
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http://dx.doi.org/10.1016/S2152-2650(20)30466-3DOI Listing
September 2020

Evidence for separate transformation to acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm from a shared ancestral hematopoietic clone.

Leuk Lymphoma 2020 09 4;61(9):2258-2261. Epub 2020 May 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1080/10428194.2020.1755856DOI Listing
September 2020

Blastic Plasmacytoid Dendritic Cell Neoplasm in 2020 and Beyond.

Authors:
Andrew A Lane

Hematol Oncol Clin North Am 2020 06 20;34(3):xiii-xiv. Epub 2020 Mar 20.

BPDCN Center, Division of Hematologic Neoplasia, Division of Adult Leukemia, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Mayer 413, Boston, MA 02215, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hoc.2020.02.011DOI Listing
June 2020

Novel Therapies for Blastic Plasmacytoid Dendritic Cell Neoplasm.

Authors:
Andrew A Lane

Hematol Oncol Clin North Am 2020 06 18;34(3):589-600. Epub 2020 Mar 18.

BPDCN Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Mayer 413, Boston, MA 02215, USA. Electronic address:

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan hematologic malignancy with poor outcomes. Tagraxofusp (SL-401) was the first drug approved specifically for patients with BPDCN, in 2018. Additional therapeutic strategies are still needed to improve survival and minimize treatment-related toxicity. This article outlines novel targeted approaches that are in preclinical or clinical development for BPDCN. Although there is no known targetable genetic abnormality that defines BPDCN, data from functional testing of primary tumors, gene expression analyses, and adaptation of targeted drug approaches from other cancers to BPDCNs harboring specific mutations have nominated several promising strategies.
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http://dx.doi.org/10.1016/j.hoc.2020.01.007DOI Listing
June 2020

Comprehensive metagenomic analysis of blastic plasmacytoid dendritic cell neoplasm.

Blood Adv 2020 03;4(6):1006-1011

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from plasmacytoid dendritic cells (pDCs), the immune cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel cell polyomavirus in Merkel cell carcinoma, human papillomavirus in head and neck squamous cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
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http://dx.doi.org/10.1182/bloodadvances.2019001260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094006PMC
March 2020

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity.

Nat Commun 2020 03 16;11(1):1406. Epub 2020 Mar 16.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.
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http://dx.doi.org/10.1038/s41467-020-15221-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076002PMC
March 2020

Tagraxofusp, the first CD123-targeted therapy and first targeted treatment for blastic plasmacytoid dendritic cell neoplasm.

Expert Rev Clin Pharmacol 2019 Oct 1;12(10):941-946. Epub 2019 Oct 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

: CD123 or interleukin 3 receptor alpha is overexpressed in multiple hematologic malignancies. Tagraxofusp is an intravenously administered CD123-directed cytotoxin consisting of the fusion of interleukin-3 with a truncated diphtheria toxin payload and was recently approved by the Food and Drug Administration for the treatment of adults and children aged 2 and older with blastic plasmacytoid dendritic cell neoplasm (BPDCN). : In this review, we discuss the use of tagraxofusp in BPDCN, and active clinical trials involving this agent in several hematologic malignancies are also presented. Tagraxofusp has significant efficacy in patients with BPDCN and manageable safety profile, with the most commonly reported adverse events being asymptomatic elevation of alanine and aspartate aminotransferase levels, hypoalbuminemia, peripheral edema, and thrombocytopenia. The most serious side effect is capillary leak syndrome that can be lethal in some cases but the risk may be mitigated by early recognition and intervention. : Tagraxofusp has been introduced as a novel treatment of BPDCN, a rare hematologic malignancy, for which no standard therapy previously existed. Many patients treated with this agent were able to be bridged to stem cell transplantation, including older patients. In the future, combinations of tagraxofusp with other targeted agents will be explored.
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http://dx.doi.org/10.1080/17512433.2019.1662297DOI Listing
October 2019

DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance.

J Clin Invest 2019 11;129(11):5005-5019

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.
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http://dx.doi.org/10.1172/JCI128571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819120PMC
November 2019

Blastic Plasmacytoid Dendritic Cell Neoplasm-Current Insights.

Clin Lymphoma Myeloma Leuk 2019 09 13;19(9):545-554. Epub 2019 Jun 13.

Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare clonal hematologic malignancy of plasmacytoid dendritic cell precursors. The presentation and clinical course of BPDCN is widely heterogeneous and was most recently categorized as a distinct clinical entity by the World Health Organization in 2016. The expanded understanding of the pathobiology of BPDCN has improved diagnostic accuracy and informed novel targeted therapeutic options. The United States Food and Drug Administration-approval of tagraxofusp (SL-401) in December 2018 has focused attention on this leukemia frequently associated with skin involvement. Herein, we aim to: (1) review etiology; (2) summarize diagnostic criteria; and (3) discuss historic treatments and novel therapies for BPDCN.
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http://dx.doi.org/10.1016/j.clml.2019.06.002DOI Listing
September 2019

Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark.

Blood 2019 08 26;134(8):678-687. Epub 2019 Jun 26.

Dana-Farber Cancer Institute, and.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.
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http://dx.doi.org/10.1182/blood.2019001144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706810PMC
August 2019

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Nature 2019 05 8;569(7757):503-508. Epub 2019 May 8.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.
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http://dx.doi.org/10.1038/s41586-019-1186-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697103PMC
May 2019

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.

Cell Res 2019 06 25;29(6):446-459. Epub 2019 Apr 25.

Cancer Research Institute, Beth Israel Deaconess Cancer Center; Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.
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http://dx.doi.org/10.1038/s41422-019-0162-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796925PMC
June 2019

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm.

N Engl J Med 2019 04;380(17):1628-1637

From the University of Texas M.D. Anderson Cancer Center, Houston (N.P., M.D., H.M.K., M.K.); Dana-Farber Cancer Institute (A.A.L.) and Boston University School of Medicine (J.M.S.), Boston, and Veristat, Southborough (J.B.) - all in Massachusetts; H. Lee Moffitt Cancer Center, Tampa, FL (K.L.S., J.E.L.); City of Hope National Medical Center, Duarte, CA (A.S.S.); Ohio State University, Columbus (S.V.); Winship Cancer Institute of Emory University, Atlanta (W.B.); Duke University Medical Center, Durham, NC (D.A.R.); and Roswell Park Comprehensive Cancer Center, Buffalo (E.S.W.), and Stemline Therapeutics, New York (S. Spence, S. Shemesh, C.L.B., I.B.) - both in New York.

Background: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.

Methods: In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response.

Results: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.

Conclusions: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).
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http://dx.doi.org/10.1056/NEJMoa1815105DOI Listing
April 2019

Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity.

Cell 2019 03 28;176(6):1265-1281.e24. Epub 2019 Feb 28.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2019.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515904PMC
March 2019

More on Blastic Plasmacytoid Dendritic-Cell Neoplasms.

N Engl J Med 2019 02;380(7):695-6

Dana–Farber Cancer Institute, Boston, MA

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http://dx.doi.org/10.1056/NEJMc1814963DOI Listing
February 2019

Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression.

Cell Rep 2018 11;25(7):1898-1911.e5

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address:

Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted.
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http://dx.doi.org/10.1016/j.celrep.2018.10.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321629PMC
November 2018

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) on Social Media: #BPDCN-Increasing Exposure over Two Years Since Inception of a Disease-Specific Twitter Community.

Curr Hematol Malig Rep 2018 12;13(6):581-587

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose Of Review: Engagement on social media for professional, healthcare-related communication is rapidly rising around the world. We aimed to better understand the dynamics of a rare disease Twitter hashtag community.

Recent Findings: Twitter has served as a platform for academic discussion, a method for knowledge dissemination directly from medical meetings, and a venue for patient caregiver and support groups. One example of a rare cancer that has seen an increase in available information via Twitter is blastic plasmacytoid dendritic cell neoplasm, or BPDCN. This field has recently experienced a new wave of interest from various healthcare stakeholders in light of key new scientific breakthroughs and novel clinical trials now starting to be available. In order to bring all relevant healthcare stakeholders together, the investigators of this article created a disease-specific Twitter community: #BPDCN = "blastic plasmacytoid dendritic cell neoplasm on social media" which has led to higher levels of engagement and discussion in the field. This article focuses on our analysis of advanced Twitter user-metrics in the second year of #BPDCN and discusses future directions for this rare cancer online disease community.
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http://dx.doi.org/10.1007/s11899-018-0490-6DOI Listing
December 2018

Maternal iAMP21 acute lymphoblastic leukemia detected on prenatal cell-free DNA genetic screening.

Blood Adv 2017 Aug 15;1(19):1491-1494. Epub 2017 Aug 15.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

cfDNA sequencing for fetal aneuploidy may detect chromosomal abnormalities representative of maternal malignancy.Maternal malignancy must be considered when abnormal cfDNA sequencing for fetal aneuploidy is associated with normal fetal karyotype.
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http://dx.doi.org/10.1182/bloodadvances.2017008680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728472PMC
August 2017

Analysis of First-Year Twitter Metrics of a Rare Disease Community for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) on Social Media: #BPDCN.

Curr Hematol Malig Rep 2017 12;12(6):592-597

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose Of Review: The use of Twitter, one of the most commonly engaged social media platforms in the world, is increasing among the general public. Notably, this trend has also been observed among those involved in the healthcare field. With its ability to readily connect diverse groups of stakeholders in a given area of interest, Twitter has become a focal point for those involved in increasing awareness and information exchange in orphan disease fields. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with generally poor long-term outcomes for adult patients and no standard therapeutic guidelines. Coupled with its low incidence rate, the disease has experienced a number of name changes over the past three decades (e.g., blastic NK cell lymphoma, CD4+CD56+ hematodermic tumor), thereby historically resulting in difficulties in its clinico-pathologic diagnosis and treatment approaches. All of these factors have led to a striking gap in terms of accurate information available to patients and the general public. Therefore, there is an urgent need for the development of more venues for the dissemination of information, particularly online, for this rare cancer.

Recent Findings: In this context, we began the Twitter medical community, #BPDCN, over a year ago, to help fill this information void. Now, completing its first year of existence, we aimed to analyze the metrics of Twitter use in order to better understand and to describe the characteristics and reach in of #BPDCN, and to determine the feasibility of starting and maintaining a disease-specific hashtag community in a particularly rare cancer.
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http://dx.doi.org/10.1007/s11899-017-0422-xDOI Listing
December 2017

Monogenic Hashimoto thyroiditis associated with a variant in the thyroglobulin (TG) gene.

J Autoimmun 2018 01 21;86:116-119. Epub 2017 Sep 21.

Genetics and Genomics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States; Division of Newborn Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.

Background: Risk of autoimmune thyroid disease (AITD) is strongly heritable. Multiple genes confer increased risk for AITD, but a monogenic origin has not yet been described. We studied a family with apparent autosomal dominant, early onset Hashimoto thyroiditis.

Methods: The family was enrolled in an IRB-approved protocol. Whole exome sequencing was used to study the proband and an affected sibling. The identified variant was studied in other family members by Sanger sequencing.

Results: We identified a previously unreported splice site variant in the thyroglobulin gene (TG c.1076-1G > C). This variant was confirmed in all affected family members who underwent testing, and also noted in one unaffected child. The variant is associated with exon 9 skipping, resulting in a novel in-frame variant transcript of TG.

Conclusion: We discovered a monogenic form of AITD associated with a splice site variant in the thyroglobulin gene. This finding raises questions about the origins of thyroid autoimmunity; possible explanations include increased immunogenicity of the mutated protein or thyroid toxicity with secondary development of anti-thyroid antibodies. Further study into the effects of this variant on thyroid function and thyroid autoimmunity are warranted.
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http://dx.doi.org/10.1016/j.jaut.2017.09.003DOI Listing
January 2018

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.

Science 2017 04;356(6335)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.
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http://dx.doi.org/10.1126/science.aah4573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775029PMC
April 2017

Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax.

Cancer Discov 2017 02 16;7(2):156-164. Epub 2016 Dec 16.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.

Significance: Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
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http://dx.doi.org/10.1158/2159-8290.CD-16-0999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296248PMC
February 2017

Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.

Nat Genet 2017 01 21;49(1):10-16. Epub 2016 Nov 21.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.
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http://dx.doi.org/10.1038/ng.3726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206905PMC
January 2017

Social Media and Internet Resources for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).

Curr Hematol Malig Rep 2016 12;11(6):462-467

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

The incorporation of Internet resources and the use of social media among patients, clinicians, advocates, and researchers in the field of hematology and oncology are growing in importance. Utilization of online information sharing is rising, especially among those involved in rare blood cancer fields, which have generally featured a paucity of reliable, updated information. In particular, blastic plasmacytoid dendritic cell neoplasm (BPDCN), an uncommon, but highly aggressive hematologic malignancy, is one example of a cancer with limited information readily available to the general public. The infrequent incidence of BPDCN, the challenges in recognizing the disease and making a clinico-pathologic diagnosis, and the lack of standard therapies are some of the reasons accounting for the dearth of expert opinion, scientific publications and discussion, and accessibility of online information for patients. This article highlights social media and Internet sources available for patients and other healthcare stakeholders in the field of BPDCN and discusses our efforts to increase awareness and propagation of BPDCN electronic resources, including the founding of an online Twitter community, #BPDCN.
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http://dx.doi.org/10.1007/s11899-016-0340-3DOI Listing
December 2016

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Cancer Cell 2016 04;29(4):574-586

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.ccell.2016.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177991PMC
April 2016

Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.

Cancer Cell 2015 Jul;28(1):29-41

Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.

A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.
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http://dx.doi.org/10.1016/j.ccell.2015.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505625PMC
July 2015

Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2015 Jun 14;21(6):1046-1053. Epub 2015 Feb 14.

Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI; Center for International Blood and Marrow Transplant Research (CIBMTR®), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

There are limited data to guide the choice of high-dose therapy (HDT) regimen before autologous hematopoietic cell transplantation (AHCT) for patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL). We studied 4917 patients (NHL, n = 3905; HL, n = 1012) who underwent AHCT from 1995 to 2008 using the most common HDT platforms: carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) (n = 1730); cyclophosphamide, BCNU, and etoposide (CBV) (n = 1853); busulfan and cyclophosphamide (BuCy) (n = 789); and total body irradiation (TBI)-containing treatment (n = 545). CBV was divided into CBV(high) and CBV(low) based on BCNU dose. We analyzed the impact of regimen on development of idiopathic pulmonary syndrome (IPS), transplantation-related mortality (TRM), and progression-free and overall survival. The 1-year incidence of IPS was 3% to 6% and was highest in recipients of CBV(high) (hazard ratio [HR], 1.9) and TBI (HR, 2.0) compared with BEAM. One-year TRM was 4% to 8%, respectively, and was similar between regimens. Among patients with NHL, there was a significant interaction between histology, HDT regimen, and outcome. Compared with BEAM, CBV(low) (HR, .63) was associated with lower mortality in follicular lymphoma (P < .001), and CBV(high) (HR, 1.44) was associated with higher mortality in diffuse large B cell lymphoma (P = .001). For patients with HL, CBV(high) (HR, 1.54), CBV(low) (HR, 1.53), BuCy (HR, 1.77), and TBI (HR, 3.39) were associated with higher mortality compared with BEAM (P < .001). The impact of specific AHCT regimen on post-transplantation survival is different depending on histology; therefore, further studies are required to define the best regimen for specific diseases.
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http://dx.doi.org/10.1016/j.bbmt.2015.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426014PMC
June 2015