Publications by authors named "Joseph Tripodi"

21 Publications

  • Page 1 of 1

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea.

Blood 2019 10;134(18):1498-1509

Department of Population Health and.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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http://dx.doi.org/10.1182/blood.2019000428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839950PMC
October 2019

Multipotent fetal-derived Cdx2 cells from placenta regenerate the heart.

Proc Natl Acad Sci U S A 2019 06 20;116(24):11786-11795. Epub 2019 May 20.

Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.
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http://dx.doi.org/10.1073/pnas.1811827116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576083PMC
June 2019

A Novel t(1;9)(p36;p24.1) JAK2 Translocation and Review of the Literature.

Acta Haematol 2019 7;142(2):105-112. Epub 2019 May 7.

Departments of Medicine and Pathology, Tumor Cytogenomics, Icahn School of Medicine at Mount Sinai Hospital, New York, New York, USA,

The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.
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http://dx.doi.org/10.1159/000498945DOI Listing
February 2020

Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53.

Blood Adv 2018 12;2(24):3581-3589

Tisch Cancer Institute, Division of Hematology/Oncology, and.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for and , respectively, and chromosome 17, where the gene for is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in / transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of , had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.
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http://dx.doi.org/10.1182/bloodadvances.2018024018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306879PMC
December 2018

Genomic characterization of spleens in patients with myelofibrosis.

Haematologica 2018 10 10;103(10):e446-e449. Epub 2018 May 10.

Myeloproliferative Neoplasms Research Program, Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Rockefeller University, New York, NY, USA

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http://dx.doi.org/10.3324/haematol.2018.193763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165826PMC
October 2018

Reappraising hyalinizing clear cell carcinoma: A population-based study with molecular confirmation.

Head Neck 2017 03 29;39(3):503-511. Epub 2016 Nov 29.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Hyalinizing clear cell carcinoma (HCCC) is a rare malignancy, characterized by EWSR1-ATF1 gene fusion, whose behavior is poorly understood, as it was for many years considered a diagnosis of exclusion.

Methods: All available salivary gland carcinomas (n = 594) from our institution were reviewed. Diagnosis of HCCC was confirmed by fluorescence in situ hybridization (FISH) for EWSR1. Literature review was performed.

Results: We found 15 patients with HCCCs (10 women, 5 men), 13 with EWSR1 rearrangement. Median age at diagnosis was 57 years (range, 31-87 years). Oral cavity (n = 9) and base of tongue (n = 4) were the most frequent primary sites. Combining our cases with those identified in literature review, the 10-year risk of local recurrence and locoregional nodal metastasis were 49% and 15%, respectively.

Conclusion: Molecularly confirmed HCCC accounted for 2.5% of salivary gland malignancies at our institution. HCCCs are indolent tumors with a propensity for locoregional recurrence. © 2016 Wiley Periodicals, Inc. Head Neck 39: 503-511, 2017.
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http://dx.doi.org/10.1002/hed.24637DOI Listing
March 2017

Analysis of ALK gene in 133 patients with breast cancer revealed polysomy of chromosome 2 and no ALK amplification.

Springerplus 2015 21;4:439. Epub 2015 Aug 21.

Department of Pathology and Laboratory Medicine, The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1194, New York, NY 10029 USA.

ALK has emerged as a novel tumorigenic factor in several epithelial human cancers. Crizotinib, an ALK tyrosine kinase inhibitor, is currently approved to treat lung cancer patients exhibiting ALK gene rearrangements. Our goal was to determine the incidence of ALK aberrations in relation to different breast cancer types. Tissue micro-arrays were constructed of ER+/PR±/HER2- (n = 37), ER-/PR-/HER2+ (n = 15), ER-/PR-/HER2- (n = 61) and ER+/PR+/HER2+ (n = 20) breast cancers; including 13 inflammatory breast carcinomas. FISH was performed using ALK break-apart and chromosome 2 centromere enumeration probes (CEP2). Neither ALK rearrangements nor amplification were identified in the 133 breast cancer cases evaluated. However, copy number gains (CNG) of ALK were identified in 82 of 133 patients (62 %). The CEP2 analysis revealed polysomy of chromosome 2 in all HCNG and LCNG cases, indicating the CNG of ALK are due to polysomy of chromosome 2, rather than true amplification of ALK. To conclude, we observed CNG of ALK secondary to chromosome 2 polysomy in a significant percentage of breast cancer cases, a phenomenon similar to polysomy 17. This study is one of the largest studies to have investigated ALK aberrations in breast cancer and the only study to include all subtypes.
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http://dx.doi.org/10.1186/s40064-015-1235-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544610PMC
August 2015

Double minute amplification of mutant PDGF receptor α in a mouse glioma model.

Sci Rep 2015 Feb 16;5:8468. Epub 2015 Feb 16.

1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029 [3] Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

In primary brain tumors, oncogenes are frequently amplified and maintained on extrachromosomal DNA as double minutes (DM), but the underlying mechanisms remain poorly understood. We have generated a mouse model of malignant glioma based on knock-in of a mutant PDGF receptor α (PDGFRα) that is expressed in oligodendrocyte precursor cells (OPCs) after activation by a Cre recombinase. In the tumor suppressor INK4/Arf(-/-) background, mutant animals frequently developed brain tumors resembling anaplastic human gliomas (WHO grade III). Besides brain tumors, most animals also developed aggressive fibrosarcomas, likely triggered by Cre activation of mutant PDGFRα in fibroblastic cell lineages. Importantly, in the brain tumors and cell lines derived from brain tumor tissues, we identified a high prevalence of DM Pdgfra gene amplification, suggesting its occurrence as an early mutational event contributing to the malignant transformation of OPCs. Amplicons extended beyond the Pdgfra locus and included in some cases neighboring genes Kit and Kdr. Our genetically defined mouse brain tumor model therefore supports OPC as a cell of origin for malignant glioma and offers an example of a defined temporal sequence of mutational events, thus providing an entry point for a mechanistic understanding of DM gene amplification and its functionality in gliomagenesis.
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http://dx.doi.org/10.1038/srep08468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329559PMC
February 2015

JAK2 inhibitors do not affect stem cells present in the spleens of patients with myelofibrosis.

Blood 2014 Nov 5;124(19):2987-95. Epub 2014 Sep 5.

Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.

Dysregulation of Janus kinase (JAK)-signal transducer and activator of transcription signaling is central to the pathogenesis of myelofibrosis (MF). JAK2 inhibitor therapy in MF patients results in a rapid reduction of the degree of splenomegaly, yet the mechanism underlying this effect remains unknown. The in vitro treatment of splenic and peripheral blood MF CD34(+) cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34(+), CD34(+)CD90(+), and CD34(+)CXCR4(+) cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutational status. Furthermore, AZD1480 treatment resulted in only a modest reduction in the proportion of HPCs that were JAK2V617F(+) or had a chromosomal abnormality. To study the effect of the drug on MF stem cells (MF-SCs), splenic CD34(+) cells were treated with AZD1480 and transplanted into immunodeficient mice. JAK2 inhibitor therapy did not affect the degree of human cell chimerism or the proportion of malignant donor cells. These data indicate that JAK2 inhibitor treatment affects a subpopulation of MF-HPCs, while sparing another HPC subpopulation as well as MF-SCs. This pattern of activity might account for the reduction in spleen size observed with JAK2 inhibitor therapy as well as the rapid increase in spleen size observed frequently with its discontinuation.
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http://dx.doi.org/10.1182/blood-2014-02-558015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224194PMC
November 2014

Spleens of myelofibrosis patients contain malignant hematopoietic stem cells.

J Clin Invest 2012 Nov;122(11):3888-99

Division of Hematology/Oncology, Pathology and Surgery, Tisch Cancer Institute, Myeloproliferative Disorders Research Consortium, Mount Sinai School of Medicine, New York, New York 10029, USA.

Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rγ(null)) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells.
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http://dx.doi.org/10.1172/JCI64397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484080PMC
November 2012

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells.

Blood 2012 Oct 7;120(15):3098-105. Epub 2012 Aug 7.

Division of Hematology/Oncology, Tisch Cancer Institute and Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.

Interferon (IFN-α) is effective therapy for polycythemia vera (PV) patients, but it is frequently interrupted because of adverse events. To permit the long-term use of IFN, we propose combining low doses of IFN with Nutlin-3, an antagonist of MDM2, which is also capable of promoting PV CD34(+) cell apoptosis. Combination treatment with subtherapeutic doses of Peg IFN-α 2a and Nutlin-3 inhibited PV CD34(+) cell proliferation by 50% while inhibiting normal CD34(+) cells by 30%. Combination treatment with Nutlin-3 and Peg IFN-α 2a inhibited PV colony formation by 55%-90% while inhibiting normal colony formation by 22%-30%. The combination of these agents also decreased the proportion of JAK2V617F-positive hematopoietic progenitor cells in 6 PV patients studied. Treatment with low doses of Peg IFN-α 2a combined with Nutlin-3 increased phospho-p53 and p21 protein levels in PV CD34(+) cells and increased the degree of apoptosis. These 2 reagents affect the tumor suppressor p53 through different pathways with Peg IFN-α 2a activating p38 MAP kinase and STAT1, leading to increased p53 transcription, whereas Nutlin-3 prevents the degradation of p53. These data suggest that treatment with low doses of both Nutlin-3 combined with Peg IFN-α 2a can target PV hematopoietic progenitor cells, eliminating the numbers of malignant hematopoietic progenitor cells.
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http://dx.doi.org/10.1182/blood-2012-02-410712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471518PMC
October 2012

Oncogene-mediated alterations in chromatin conformation.

Proc Natl Acad Sci U S A 2012 Jun 21;109(23):9083-8. Epub 2012 May 21.

Department of Pathology and Laboratory Medicine, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.

Emerging evidence suggests that chromatin adopts a nonrandom 3D topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra- and interchromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding, and gene expression, we demonstrate that oncogenic transcription factor overexpression is associated with global, reproducible, and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression, e.g., EWS-FLI1, c-Myc, n-Myc, and PML-RARα.
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http://dx.doi.org/10.1073/pnas.1112570109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384175PMC
June 2012

Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation.

Circ Res 2012 Jan 14;110(1):82-93. Epub 2011 Nov 14.

Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1030, New York, NY 10029, USA.

Rationale: Fetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras.

Objective: Based on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells.

Methods And Results: We report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta.

Conclusions: Fetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.249037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365532PMC
January 2012

Multiploid inheritance of HIV-1 during cell-to-cell infection.

J Virol 2011 Jul 4;85(14):7169-76. Epub 2011 May 4.

Division of Infectious Diseases, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1630, New York, NY 10029, USA.

During cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1), many viral particles can be simultaneously transferred from infected to uninfected CD4 T cells through structures called virological synapses (VS). Here we directly examine how cell-free and cell-to-cell infections differ from infections initiated with cell-free virus in the number of genetic copies that are transmitted from one generation to the next, i.e., the genetic inheritance. Following exposure to HIV-1-expressing cells, we show that target cells with high viral uptake are much more likely to become infected. Using T cells that coexpress distinct fluorescent HIV-1 variants, we show that multiple copies of HIV-1 can be cotransmitted across a single VS. In contrast to cell-free HIV-1 infection, which titrates with Poisson statistics, the titration of cell-associated HIV-1 to low rates of overall infection generates a constant fraction of the newly infected cells that are cofluorescent. Triple infection was also readily detected when cells expressing three fluorescent viruses were used as donor cells. A computational model and a statistical model are presented to estimate the degree to which cofluorescence underestimates coinfection frequency. Lastly, direct detection of HIV-1 proviruses using fluorescence in situ hybridization confirmed that significantly more HIV-1 DNA copies are found in primary T cells infected with cell-associated virus than in those infected with cell-free virus. Together, the data suggest that multiploid inheritance is common during cell-to-cell HIV-1 infection. From this study, we suggest that cell-to-cell infection may explain the high copy numbers of proviruses found in infected cells in vivo and may provide a mechanism through which HIV preserves sequence heterogeneity in viral quasispecies through genetic complementation.
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http://dx.doi.org/10.1128/JVI.00231-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126592PMC
July 2011

Development of t(8;21) and RUNX1-RUNX1T1 in the Philadelphia-positive clone of a patient with chronic myelogenous leukemia: additional evidence for multiple steps involved in disease progression.

Cancer Genet 2011 Mar;204(3):165-70

Tumor Cytogenetics Laboratory, Department of Pathology, The Myeloproliferative Program, Tisch Cancer Center, The Mount Sinai School of Medicine, New York, New York, USA.

A 65-year-old patient with a high hemoglobin and hematocrit was treated for 14 months with therapeutic phlebotomy when cytogenetics of bone marrow revealed 100% cells with the Ph chromosome and 45% of the Ph+ cells contained trisomy 8. Treatment with tyrosine kinase inhibitors did not reduce the BCR-ABL1 fusion positive clone. Instead, the Ph positive cells acquired further the t(8;21)/RUNX1-RUNX1T1, del(4q) and trisomy 15 chromosomal abnormalities which were resistant to further treatment. Literature review revealed eight other patients who either had t(9;22) and t(8;21) simultaneously or developed t(8;21) in the Ph positive clone. We conclude that there are rare patients with CML who either present in blast crisis with coexistence of t(9;22) and t(8;21) with or without +8, or progress to blast crisis with acquiring RUNX1-RUNX1T1 in the BCR-ABL1 clone which may or may not be therapy related and represent a later event in a multistep pathogenesis.
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http://dx.doi.org/10.1016/j.cancergencyto.2010.09.001DOI Listing
March 2011

Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production.

Blood 2011 Apr 1;117(17):4580-9. Epub 2011 Mar 1.

Division of Hematology and Medical Oncology, Department of Medicine, and Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.

The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis.
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http://dx.doi.org/10.1182/blood-2010-09-305540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099574PMC
April 2011

Frequency of heterozygous TET2 deletions in myeloproliferative neoplasms.

Cancer Manag Res 2010 Sep 17;2:219-23. Epub 2010 Sep 17.

The Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine and.

The Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a group of clonal hematopoietic stem cell disorders with overlapping clinical and cytogenetic features and a variable tendency to evolve into acute leukemia. These diseases not only share overlapping chromosomal abnormalities but also a number of acquired somatic mutations. Recently, mutations in a putative tumor suppressor gene, ten-eleven translocation 2 (TET2) on chromosome 4q24 have been identified in 12% of patients with MPN. Additionally 4q24 chromosomal rearrangements in MPN, including TET2 deletions, have also been observed using conventional cytogenetics. The goal of this study was to investigate the frequency of genomic TET2 rearrangements in MPN using fluorescence in situ hybridization as a more sensitive method for screening and identifying genomic deletions. Among 146 MPN patients, we identified two patients (1.4%) who showed a common 4q24 deletion, including TET2. Our observations also indicated that the frequency of TET2 deletion is increased in patients with an abnormal karyotype (5%).
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http://dx.doi.org/10.2147/CMR.S12829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004566PMC
September 2010

Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells.

Blood 2010 Dec 21;116(26):5972-82. Epub 2010 Sep 21.

Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.

Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34(+) cells. Treatment of PMF CD34(+) cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34(+) chemokine (C-X-C motif) receptor (CXCR)4(+) cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F(+). Furthermore, sequential treatment of PMF CD34(+) cells but not normal CD34(+) cells with decitabine (5-aza-2'-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F(+) PMF CD34(+) cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγ(null) mice, the percentage of JAK2V617F/JAK2(total) in human CD45(+) marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F(+) and that JAK2V617F(+) HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC.
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http://dx.doi.org/10.1182/blood-2010-02-269696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031385PMC
December 2010

Contemplations on preclinical validation of fluorescence in situ hybridization probe assay for paraffin-embedded tissues in hematologic disorders.

Cancer Genet Cytogenet 2008 May;183(1):1-5

Genzyme Genetics, New York 10019, USA.

A validation of fluorescence in situ hybridization (FISH) assays for paraffin-embedded tissues (PET) is required before clinical use. Although the FISH probe validation process for hematologic disorders has been described during recent years, none of these descriptions, to our knowledge, address the validation process for paraffin-embedded tissues in detail. We describe an applicable preclinical validation process. The following five-step validation is outlined: (1) pathologist's review of slide; (2) probe validation on metaphases to assess sensitivity and specificity; (3) a pilot study using FISH probes on PET; (4) analytical validation using normal and abnormal PET samples to establish a normal reference range or cutoff; and (5) application of the cutoffs to test samples. Although the procedure focuses on dual-color, dual-fusion FISH assays, the same steps could be used for any type of probe. We have described a preclinical validation for probes on paraffin-embedded tissue.
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http://dx.doi.org/10.1016/j.cancergencyto.2008.01.015DOI Listing
May 2008
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