Publications by authors named "Duane Hassane"

32 Publications

Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.

Cell 2020 Nov;183(5):1162-1184

KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.
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http://dx.doi.org/10.1016/j.cell.2020.10.050DOI Listing
November 2020

Clonal Hematopoiesis Before, During, and After Human Spaceflight.

Cell Rep 2020 Dec 25;33(10):108458. Epub 2020 Nov 25.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, 10065, USA; The Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, New York, NY, USA; The Feil Family Brain and Mind Research Institute, New York, NY, USA. Electronic address:

Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.
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http://dx.doi.org/10.1016/j.celrep.2020.108458DOI Listing
December 2020

Plasma Cell Myeloma Presenting With Amyloid-Laden Crystal-Negative Histiocytosis.

Am J Clin Pathol 2020 11;154(6):767-775

Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY.

Objectives: Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident with multiple myeloma and amyloidosis have been reported previously.

Methods: A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH.

Results: The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months.

Conclusions: We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.
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http://dx.doi.org/10.1093/ajcp/aqaa095DOI Listing
November 2020

Cranberry A-type proanthocyanidins selectively target acute myeloid leukemia cells.

Blood Adv 2019 11;3(21):3261-3265

Department of Medicine, Weill Cornell Medical College, New York, NY.

Most elderly patients affected with acute myeloid leukemia (AML) will relapse and die of their disease even after achieving complete remission, thus emphasizing the urgent need for new therapeutic approaches with minimum toxicity to normal hematopoietic cells. Cranberry (Vaccinium spp.) extracts have exhibited anticancer and chemopreventive properties that have been mostly attributed to A-type proanthocyanidin (A-PAC) compounds. A-PACs, isolated from a commercially available cranberry extract, were evaluated for their effects on leukemia cell lines, primary AML samples, and normal CD34+ cord blood specimens. Our results indicated potent and specific antileukemia activity in vitro. In addition, the antileukemia activity of A-PACs extended to malignant progenitor and stem cell populations, sparing their normal counterparts. The antileukemia effects of A-PACs were also observed in vivo using patient derived xenografts. Surprisingly, we found that the mechanism of cell death was driven by activation of NF-κB. Overall, our data suggest that A-PACs could be used to improve treatments for AML by targeting leukemia stem cells through a potentially novel pathway.
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http://dx.doi.org/10.1182/bloodadvances.2018026633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855100PMC
November 2019

Clonal Hematopoiesis and Premalignant Diseases.

Cold Spring Harb Perspect Med 2020 04 1;10(4). Epub 2020 Apr 1.

Division of Hematology & Oncology, Weill Cornell Medical College, New York, New York 10065, USA.

Clonal hematopoiesis (CH) arises when mutations in the hematopoietic system confer a fitness advantage to specific clones, thereby favoring their disproportionate growth. The presence of CH increases with age and environmental exposures such as cytotoxic chemotherapy or radiotherapy. The most frequent mutations occur in epigenetic regulators, such as , , and , leading to dysregulation of tumor suppressor function, pathogen response, and inflammation. These dysregulated processes elevate risk of overall mortality, cardiovascular disease, and eventual hematologic malignancy (HM). CH is likely acting as an initiating event leading to HM when followed by cooperating mutations. However, further evidence suggests that CH exerts a bystander influence through its pro-inflammatory properties. Delineating the mechanisms that lead to the onset and expansion of CH as well as its contribution to risk of HM is crucial to defining a management and intervention strategy. In this review, we discuss the potential causes, consequences, technical considerations, and possible management strategies for CH in the context of HMs and pre-HMs.
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http://dx.doi.org/10.1101/cshperspect.a035675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117948PMC
April 2020

Clonal Hematopoiesis and risk of Acute Myeloid Leukemia.

Best Pract Res Clin Haematol 2019 06 24;32(2):177-185. Epub 2019 May 24.

Division of Hematology & Oncology, Weill Cornell Medicine, New York, NY, USA.

Acute Myeloid Leukemia, the most common form of acute leukemia in adults, is an aggressive hematopoietic stem cell malignancy that is associated with significant morbidity and mortality. Though AML generally presents de novo, risk factors include exposure to chemotherapy and/or radiation, as well as both familial and acquired bone marrow failure syndromes. Clonal Hematopoiesis (CH) refers to an expansion of blood or marrow cells resulting from somatic mutations in leukemia-associated genes detected in individuals without cytopenias or hematological malignancies. While CH is considered part of normal ageing, CH is also significantly associated with cardiovascular disease, solid tumors, and hematological malignancies. In this review, we will discuss evidence linking CH with the development of AML, as well as describe challenges in and strategies for monitoring patients with high risk CH mutations.
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http://dx.doi.org/10.1016/j.beha.2019.05.007DOI Listing
June 2019

Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance).

Blood Adv 2018 12;2(24):3608-3617

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Novel treatment strategies are needed for older patients with acute myeloid leukemia (AML). This randomized phase 2 trial compared the efficacy and safety of 20 mg/m of IV decitabine on days 1 to 10 alone (arm A) with those of 1.3 mg/m of subcutaneous bortezomib (arm B) on days 1, 4, 8, and 11 for up to 4 10-day cycles followed by monthly 5-day cycles. Previously untreated AML patients age ≥60 years (excluding those with mutations and favorable-risk cytogenetics) without restrictions in performance status (PS) or organ function were eligible. Median age was 72.4 years (range, 60.5-92.3 years); 31 patients (19%) had baseline PS ≥2, 35 (22%) had an antecedent hematological disorder, 58 had (39%) adverse cytogenetics, and 7 (5%) and 23 (14%) had abnormal cardiac or renal function. There were no statistically significant differences in overall survival (OS) or responses between the 2 treatment arms. The overall response rate (complete remission + complete remission with incomplete blood count recovery) was 39% (n = 64), with median OS of 9.3 months. Nineteen responders (31%) underwent allogeneic stem cell transplantation. The most common adverse event was febrile neutropenia, and there were no unexpected toxicities. Adding bortezomib to decitabine did not improve outcomes, but responses were better than those in previous trials using 5-day decitabine cycles. This trial was registered at www.clinicaltrials.gov as #NCT01420926.
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http://dx.doi.org/10.1182/bloodadvances.2018023689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306886PMC
December 2018

Somatic mutations precede acute myeloid leukemia years before diagnosis.

Nat Med 2018 07 9;24(7):1015-1023. Epub 2018 Jul 9.

Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.

The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
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http://dx.doi.org/10.1038/s41591-018-0081-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849383PMC
July 2018

Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia.

Haematologica 2018 08 3;103(8):1308-1316. Epub 2018 May 3.

Division of Hematology and Medical Oncology, Leukemia Program, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY, USA.

Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m days 1-10 and escalating doses of plerixafor (320-810 mcg/kg) days 1-5. Sixty-nine patients were treated, with an overall response rate of 43%. Adverse karyotype did not predict response (=0.31). Prior hypomethylating agent treatment was the strongest independent predictor of adverse overall survival (hazard ratio 3.1; 95%CI: 1.3-7.3; =0.008) and response (14% in previously treated patients, 46% in treatment naïve; =0.002). As expected, the most common toxicities were myelosuppression and infection. Plerixafor induced mobilization of leukemia stem and progenitor cells, but did not cause clinically significant hyperleukocytosis. Reduction in leukemia stem cells appeared to correlate with duration of response. Plerixafor can be safely added to decitabine in poor-prognosis, elderly acute myeloid leukemia patients. The maximum tolerated dose of the combination was 810 mcg/kg. While mobilization of leukemia stem cells was observed in some patients, the clinical benefit of adding plerixafor was uncertain. This trial was registered at .
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http://dx.doi.org/10.3324/haematol.2017.183418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068018PMC
August 2018

Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites.

Nature 2017 11 25;551(7678):95-99. Epub 2017 Sep 25.

Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York, USA.

Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes. Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite and ends, 48 hours later, with a schizont releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes. Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600), the master regulator of sexual development, from an epigenetically silenced state during asexual replication. AP2-G expression during this 'commitment cycle' prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism. To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1-30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling. Here we use highly parallel, single-cell RNA sequencing of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histone-modifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.
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http://dx.doi.org/10.1038/nature24280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055935PMC
November 2017

Myelodysplastic Syndrome, Unclassifiable (MDS-U) With 1% Blasts Is a Distinct Subgroup of MDS-U With a Poor Prognosis.

Am J Clin Pathol 2017 Jul;148(1):49-57

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY.

Objectives: Three situations qualify as myelodysplastic syndrome, unclassifiable (MDS-U): (1) refractory cytopenia with dysplasia and 1% blasts in peripheral blood (BL), (2) pancytopenia with unilineage dysplasia (Pan), and (3) persistent cytopenia, less than 5% bone marrow blasts, and less than 10% dysplastic cells and presence of MDS-defining cytogenetic abnormalities (CG). We compared the clinicopathologic features and mutational profiles for these three groups.

Methods: MDS-U cases were reviewed at four major academic institutions. Targeted next-generation sequencing for genes implicated in myeloid neoplasms was performed in a subset of cases.

Results: Twenty-seven patients were identified (six MDS-U BL, 13 MDS-U Pan, and eight MDS-U CG). Clonal cytogenetic abnormalities were found in six of six, seven of 13, and eight of eight cases in MDS-U BL, Pan, and CG, respectively (P > .05). Overall, four of six patients with MDS-U BL progressed to acute myeloid leukemia; no MDS-U Pan or CG patients did. The rates of progression-free survival and mortality (overall survival) were significantly higher in MDS-U BL compared with Pan and CG (P < .001 for both).

Conclusions: We find that MDS-U BL is a distinct subset of MDS-U with a poor prognosis, while MDS-U Pan and CG are relatively indolent. Evaluation of peripheral blood smears in patients with MDS is essential for accurate classification and prognosis.
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http://dx.doi.org/10.1093/ajcp/aqx043DOI Listing
July 2017

CD25 expression and outcomes in older patients with acute myelogenous leukemia treated with plerixafor and decitabine.

Leuk Lymphoma 2018 04 18;59(4):821-828. Epub 2017 Jul 18.

a Department of Medicine, Division of Hematology and Medical Oncology , Weill Cornell Medicine , New York , NY , USA.

We investigated CD25 expression in older (≥60 years) patients with new acute myelogenous leukemia treated with decitabine and plerixafor. Patients resistant to therapy or survival ≤1 year had significantly higher percentages of CD25 myeloid blasts in baseline bone marrow. CD25 patients had an increased odds of resistance compared to CD25 patients (p = .015). In univariate analysis, we found CD25 patients had inferior survival compared to CD25 (p = .002). In patients with intermediate risk cytogenetics, CD25 status stratified patients associating with inferior survival (p = .002). In multivariable analysis, CD25 and TP53 mutations trended towards predicting remission to therapy but were not predictive of survival. Only remission status, ASXL1 and TET2 mutations were found to independently predict overall survival (OS). We conclude CD25 expression identifies patients at risk for resistance to hypomethylating chemotherapy but does not independently predict OS in an older AML population treated with decitabine and plerixafor.
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http://dx.doi.org/10.1080/10428194.2017.1352089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773411PMC
April 2018

Oligomonocytic chronic myelomonocytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational profile to classical chronic myelomonocytic leukemia.

Mod Pathol 2017 09 26;30(9):1213-1222. Epub 2017 May 26.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Chronic myelomonocytic leukemia is characterized by persistent absolute monocytosis (≥1 × 10/l) in the peripheral blood and dysplasia in ≥1 lineages. In the absence of dysplasia, an acquired clonal genetic abnormality is required or causes for reactive monocytosis have to be excluded. Oligomonocytic chronic myelomonocytic leukemia showing increased monocytes but no absolute monocytosis in the peripheral blood occurs occasionally. These cases are likely classified as myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm, unclassifiable. A subset eventually develop overt chronic myelomonocytic leukemia. Better characterization of oligomonocytic chronic myelomonocytic leukemia is essential since the distinction between chronic myelomonocytic leukemia and myelodysplastic syndrome is clinically relevant. We identified 44 cases of oligomonocytic chronic myelomonocytic leukemia (≥10% peripheral blood monocytes with absolute monocyte count of 0.5-1 × 10/l) and 28 consecutive chronic myelomonocytic leukemia controls. Clinicopathologic features were compared and mutation analysis was performed. Oligomonocytic chronic myelomonocytic leukemia patients were significantly younger (median age of 65 vs 72). They had lower WBC and absolute neutrophil count, while the monocyte percentage, hemoglobin and platelet counts were similar in the two groups. The myeloid to erythroid ratio was predominantly decreased or normal, compared with the characteristic increase in chronic myelomonocytic leukemia (P=0.006). 38% of patients progressed to overt chronic myelomonocytic leukemia (median: 12 months). The overall percentage of mutations was significantly lower in oligomonocytic chronic myelomonocytic leukemia. However, the most frequent mutations in both groups were the 'signature' chronic myelomonocytic leukemia mutations in ASXL1, TET2 and SRSF2. Mutations in CBL were found exclusively in overt chronic myelomonocytic leukemia. In conclusion, we demonstrate clinical and genetic similarities between overt chronic myelomonocytic leukemia and oligomonocytic chronic myelomonocytic leukemia. The findings suggest that at least a subset of oligomonocytic chronic myelomonocytic leukemia represents early phase 'dysplastic type' chronic myelomonocytic leukemia.
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http://dx.doi.org/10.1038/modpathol.2017.45DOI Listing
September 2017

Minimal Residual Disease Monitoring of Acute Myeloid Leukemia by Massively Multiplex Digital PCR in Patients with NPM1 Mutations.

J Mol Diagn 2017 07 16;19(4):537-548. Epub 2017 May 16.

Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address:

The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis. Thus, some patients are ineligible for NPM1 MRD monitoring. Furthermore, a subset of patients with NPM1-mutated AML will have false-negative MRD results because of clonal evolution. To simplify and improve MRD testing for NPM1, we present a novel digital PCR technique composed of massively multiplex pools of insertion-specific primers that selectively detect mutated but not wild-type NPM1. By measuring reaction end points using digital PCR technology, the resulting single assay enables sensitive and specific quantification of most NPM1 exon 12 mutations in a manner that is robust to clonal heterogeneity, does not require NPM1 sequence information, and obviates the need for maintenance of hundreds of type-specific assays and associated plasmid standards.
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http://dx.doi.org/10.1016/j.jmoldx.2017.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500824PMC
July 2017

The effect of initial molecular profile on response to recombinant interferon-α (rIFNα) treatment in early myelofibrosis.

Cancer 2017 Jul 18;123(14):2680-2687. Epub 2017 May 18.

Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Background: Although recombinant interferon-α (rIFNα) effectively treats patients with early myelofibrosis, the effect of driver and high molecular risk (HMR) mutations has not been considered. In this phase 2 study, for the first time, the authors correlate response to rIFNα treatment with driver and HMR mutations.

Methods: Patients were diagnosed using World Health Organization or International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Only patients who had low or intermediate-1 Dynamic International Prognostic Scoring System scores with ≥15% hematopoietic bone marrow foci were included. History, symptom assessment, physical examination, and blood and bone marrow studies were performed. Genomic DNA was extracted from frozen cells, and next-generation targeted sequencing of 45 genes was performed. Either rIFNα-2b (0.5 million units subcutaneously 3 times weekly) or pegylated rIFNα-2a (45 μg weekly) with escalation was initiated. All patients were followed at the authors' institution, and regular bone marrow biopsies were encouraged. International Working Group for Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet treatment response criteria were used.

Results: Of 30 patients (16 women and 14 men; median age, 58 years), 22 were classified as low risk, and 8 were classified as intermediate-1 risk. Two patients achieved complete remission, 9 achieved partial remission, 4 had clinical improvement, 7 had stable disease; 3 had progressive disease, 1 relapsed, and 4 died. There were 22 patients with JAK mutations, 6 with CALR mutations, and 2 with MPL mutations. Seventy-three percent of patients improved or remained stable with acceptable toxicity, including 37% who achieved complete or partial remission. There was no correlation between treatment response and baseline driver mutations or Dynamic International Prognostic Scoring System scores. Of 8 poor responders, 3 had ASXL1 or SRSF2 mutations.

Conclusions: Early treatment with rIFNα in patients without HMR mutations may prevent the development of marked splenomegaly, anemia, and florid myelofibrosis. Molecular profiling at the time of diagnosis may predict prognosis and treatment response. Cancer 2017;123:2680-87. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30679DOI Listing
July 2017

Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.

J Clin Invest 2017 Jun 15;127(6):2066-2080. Epub 2017 May 15.

Department of Pathology and Laboratory Medicine.

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.
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http://dx.doi.org/10.1172/JCI83936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451239PMC
June 2017

Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.

Cancer Discov 2017 08 13;7(8):868-883. Epub 2017 Apr 13.

Department of Human Genetics and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.

We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in and had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double-mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in preleukemic LSK cells from or single-mutant and / double-mutant mice. Notably, double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition as compared with AMLs with either single mutation. AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities. Comprehensive DNA methylation profiling revealed that differential methylation of nonpromoter regulatory elements is a driver of epigenetic identity, that gene mutations can be context-dependent, and that co-occurrence of mutations in epigenetic modifiers can result in epigenetic antagonism. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540802PMC
August 2017

Matrix stiffening promotes a tumor vasculature phenotype.

Proc Natl Acad Sci U S A 2017 01 29;114(3):492-497. Epub 2016 Dec 29.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;

Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.
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http://dx.doi.org/10.1073/pnas.1613855114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5255592PMC
January 2017

Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.

Nat Med 2016 07 20;22(7):792-9. Epub 2016 Jun 20.

Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.

Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.
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http://dx.doi.org/10.1038/nm.4125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938719PMC
July 2016

Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia.

Mol Cancer Ther 2014 Aug 16;13(8):1979-90. Epub 2014 Jun 16.

Institute of Computational Biomedicine, Weill Medical College of Cornell University, New York;

Most patients with acute myelogenous leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSC). Thus, it is imperative to identify novel therapies that can ablate LSCs. Using an in silico gene expression-based screen for compounds evoking transcriptional effects similar to the previously described anti-LSC agent parthenolide, we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor that is structurally similar to phenylbutyrate, but with improved activity at submicromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of Hsp90 to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike parthenolide, the caspase-dependent apoptosis caused by AR-42 occurs without activation of Nrf-2-driven cytoprotective pathways. As AR-42 is already being tested in early clinical trials, we expect that our results can be extended to the clinic.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383047PMC
August 2014

Novel mTOR inhibitory activity of ciclopirox enhances parthenolide antileukemia activity.

Exp Hematol 2013 Sep 6;41(9):799-807.e4. Epub 2013 May 6.

Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA.

Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
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http://dx.doi.org/10.1016/j.exphem.2013.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809917PMC
September 2013

Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells.

Cell Stem Cell 2012 Sep 2;11(3):359-72. Epub 2012 Aug 2.

James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA.

Leukemia stem cells (LSCs) represent a biologically distinct subpopulation of myeloid leukemias, with reduced cell cycle activity and increased resistance to therapeutic challenge. To better characterize key properties of LSCs, we employed a strategy based on identification of genes synergistically dysregulated by cooperating oncogenes. We hypothesized that such genes, termed "cooperation response genes" (CRGs), would represent regulators of LSC growth and survival. Using both a primary mouse model and human leukemia specimens, we show that CRGs comprise genes previously undescribed in leukemia pathogenesis in which multiple pathways modulate the biology of LSCs. In addition, our findings demonstrate that the CRG expression profile can be used as a drug discovery tool for identification of compounds that selectively target the LSC population. We conclude that CRG-based analyses provide a powerful means to characterize the basic biology of LSCs as well as to identify improved methods for therapeutic targeting.
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http://dx.doi.org/10.1016/j.stem.2012.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023631PMC
September 2012

Acute myelogenous leukemia stem cells: from Bench to Bedside.

Cancer Lett 2013 Sep 17;338(1):4-9. Epub 2012 Jun 17.

Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, 1275 York Ave., New York, NY 10065, United States.

Despite reaching remission with traditional chemotherapy, most adult patients with acute myeloid leukemia (AML) will relapse and die of their disease. Numerous studies have identified a rare subset of leukemia cells that evade traditional chemotherapy and are capable of self-renewal and initiating leukemia. These cells are thought to be responsible for relapse and are termed leukemia stem cells (LSCs). This article will review the current LSC translational research and focus on new approaches to detect LSC burden and its prognostic implications, as well as the identification and development of therapeutic agents active against LSCs.
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http://dx.doi.org/10.1016/j.canlet.2012.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374350PMC
September 2013

Chemical genomic screening reveals synergism between parthenolide and inhibitors of the PI-3 kinase and mTOR pathways.

Blood 2010 Dec 1;116(26):5983-90. Epub 2010 Oct 1.

Department of Pathology and Laboratory Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.

We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.
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http://dx.doi.org/10.1182/blood-2010-04-278044DOI Listing
December 2010

Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data.

Blood 2008 Jun 27;111(12):5654-62. Epub 2008 Feb 27.

James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, NY, USA.

Increasing evidence indicates that malignant stem cells are important for the pathogenesis of acute myelogenous leukemia (AML) and represent a reservoir of cells that drive the development of AML and relapse. Therefore, new treatment regimens are necessary to prevent relapse and improve therapeutic outcomes. Previous studies have shown that the sesquiterpene lactone, parthenolide (PTL), ablates bulk, progenitor, and stem AML cells while causing no appreciable toxicity to normal hematopoietic cells. Thus, PTL must evoke cellular responses capable of mediating AML selective cell death. Given recent advances in chemical genomics such as gene expression-based high-throughput screening (GE-HTS) and the Connectivity Map, we hypothesized that the gene expression signature resulting from treatment of primary AML with PTL could be used to search for similar signatures in publicly available gene expression profiles deposited into the Gene Expression Omnibus (GEO). We therefore devised a broad in silico screen of the GEO database using the PTL gene expression signature as a template and discovered 2 new agents, celastrol and 4-hydroxy-2-nonenal, that effectively eradicate AML at the bulk, progenitor, and stem cell level. These findings suggest the use of multicenter collections of high-throughput data to facilitate discovery of leukemia drugs and drug targets.
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http://dx.doi.org/10.1182/blood-2007-11-126003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424160PMC
June 2008

An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells.

Blood 2007 Dec 5;110(13):4427-35. Epub 2007 Sep 5.

James P Wilmot Cancer Center, University of Rochester, NY 14642, USA.

Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kappaB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.
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http://dx.doi.org/10.1182/blood-2007-05-090621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234793PMC
December 2007

Tat-calpastatin fusion proteins transduce primary rat cortical neurons but do not inhibit cellular calpain activity.

Exp Neurol 2004 Jul;188(1):161-70

Department of Anatomy and Neurobiology, and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0230, USA.

Excessive activation of calpains (calcium-activated neutral proteases) is observed following spinal cord contusion injury, traumatic brain injury, stroke, and in neurodegenerative disorders including Alzheimer's disease. Calpain inhibition represents an attractive therapeutic target, but current calpain inhibitors possess relatively weak potency, poor specificity, and in many cases, limited cellular and blood-brain barrier permeability. We developed novel calpain inhibitors consisting of the endogenous inhibitor, calpastatin or its inhibitory domain I, fused to the protein transduction domain of the HIV trans-activator (Tat) protein (Tat(47-57)). The Tat-calpastatin fusion proteins were potent calpain inhibitors in a cell-free activity assay, but did not inhibit cellular calpain activity in primary rat cortical neurons when applied exogenously at concentrations up to 5 microM. The fusion proteins were able to transduce neurons, but were localized within endosome-like structures. A similar endosomal uptake was observed for Tat-GFP. Together, the results suggest that endosomal uptake of the Tat-calpastatin prevents its interaction with calpain in other cellular compartments. Endosomal uptake of proteins fused to the Tat protein transduction domain severely limits the applications of this methodology.
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http://dx.doi.org/10.1016/j.expneurol.2004.03.018DOI Listing
July 2004