Top

Published in:

Open Access 01-12-2014 | Research

Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients

Authors: Isabelle Bartram, Nicola Gökbuget, Cornelia Schlee, Sandra Heesch, Lars Fransecky, Stefan Schwartz, Reingard Stuhlmann, Kerstin Schäfer-Eckhart, Michael Starck, Albrecht Reichle, Dieter Hoelzer, Claudia D Baldus, Martin Neumann

Published in: Journal of Hematology & Oncology | Issue 1/2014

Abstract

Background

Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed.

Methods

We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients.

Results

We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b.

Conclusions

In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.

Available only for authorised users

Gokbuget N, Hoelzer D: Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009, 46: 64-75. 10.1053/j.seminhematol.2008.09.003.CrossRefPubMed

Hunault M, Harousseau JL, Delain M, Truchan-Graczyk M, Cahn JY, Witz F, Lamy T, Pignon B, Jouet JP, Garidi R, Caillot D, Berthou C, Guyotat D, Sadoun A, Sotto JJ, Lioure B, Casassus P, Solal-Celigny P, Stalnikiewicz L, Audhuy B, Blanchet O, Baranger L, Béné MC, Ifrah N: Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004, 104: 3028-3037. 10.1182/blood-2003-10-3560.CrossRefPubMed

Bassan R, Hoelzer D: Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011, 29: 532-543. 10.1200/JCO.2010.30.1382.CrossRefPubMed

Hoelzer D: Novel antibody-based therapies for acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Progr. 2011, 2011: 243-249. 10.1182/asheducation-2011.1.243.CrossRef

Daver N, O'Brien S: Novel therapeutic strategies in adult acute lymphoblastic leukemia - a focus on emerging monoclonal antibodies. Curr Hematol Malig Rep. 2013, 8: 123-131. 10.1007/s11899-013-0160-7.PubMedCentralCrossRefPubMed

Topp MS, Gokbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC: Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012, 120: 5185-5187. 10.1182/blood-2012-07-441030.CrossRefPubMed

Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, Billett A, Kurtzberg J, Reaman G, Gaynon P, Whitlock J, Krailo M, Harris MB: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the children’s oncology group. J Clin Oncol. 2005, 23: 3376-3382. 10.1200/JCO.2005.03.426.CrossRefPubMed

Robak T: New nucleoside analogs for patients with hematological malignancies. Expert Opin Investig Drugs. 2011, 20: 343-359. 10.1517/13543784.2011.554822.CrossRefPubMed

Palomero T, Ferrando A: Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia. Clin Lymphoma Myeloma. 2009, 9 (Suppl 3): S205-S210. 10.3816/CLM.2009.s.013.PubMedCentralCrossRefPubMed

10.

Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D: Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009, 10: 147-156. 10.1016/S1470-2045(08)70314-0.PubMedCentralCrossRefPubMed

11.

Meijerink JP: Genetic rearrangements in relation to immunophenotype and outcome in T-cell acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2010, 23: 307-318. 10.1016/j.beha.2010.08.002.CrossRefPubMed

12.

Neumann M, Heesch S, Gokbuget N, Schwartz S, Schlee C, Benlasfer O, Farhadi-Sartangi N, Thibaut J, Burmeister T, Hoelzer D, Hofmann WK, Thiel E, Baldus CD: Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations.Blood Cancer J 2012, 2:e55.

13.

Liu P, Li P, Burke S: Critical roles of Bcl11b in T-cell development and maintenance of T-cell identity. Immunol Rev. 2010, 238: 138-149. 10.1111/j.1600-065X.2010.00953.x.CrossRefPubMed

14.

Kominami R: Role of the transcription factor Bcl11b in development and lymphomagenesis. Proc Jpn Acad Ser B Phys Biol Sci. 2012, 88: 72-87. 10.2183/pjab.88.72.PubMedCentralCrossRefPubMed

15.

Cherrier T, Suzanne S, Redel L, Calao M, Marban C, Samah B, Mukerjee R, Schwartz C, Gras G, Sawaya BE, Zeichner SL, Aunis D, Van Lint C, Rohr O: p21(WAF1) gene promoter is epigenetically silenced by CTIP2 and SUV39H1. Oncogene. 2009, 28: 3380-3389. 10.1038/onc.2009.193.PubMedCentralCrossRefPubMed

16.

Cismasiu VB, Ghanta S, Duque J, Albu DI, Chen HM, Kasturi R, Avram D: BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes. Blood. 2006, 108: 2695-2702. 10.1182/blood-2006-05-021790.PubMedCentralCrossRefPubMed

17.

Topark-Ngarm A, Golonzhka O, Peterson VJ, Barrett B, Martinez B, Crofoot K, Filtz TM, Leid M: CTIP2 associates with the NuRD complex on the promoter of p57KIP2, a newly identified CTIP2 target gene. J Biol Chem. 2006, 281: 32272-32283. 10.1074/jbc.M602776200.PubMedCentralCrossRefPubMed

18.

Grabarczyk P, Przybylski GK, Depke M, Volker U, Bahr J, Assmus K, Broker BM, Walther R, Schmidt CA: Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells. Oncogene. 2007, 26: 3797-3810. 10.1038/sj.onc.1210152.CrossRefPubMed

19.

Karanam NK, Grabarczyk P, Hammer E, Scharf C, Venz S, Gesell-Salazar M, Barthlen W, Przybylski GK, Schmidt CA, Volker U: Proteome analysis reveals new mechanisms of Bcl11b-loss driven apoptosis. J Proteome Res. 2010, 9: 3799-3811. 10.1021/pr901096u.CrossRefPubMed

20.

Grabarczyk P, Nahse V, Delin M, Przybylski G, Depke M, Hildebrandt P, Volker U, Schmidt CA: Increased expression of bcl11b leads to chemoresistance accompanied by G1 accumulation.PLoS One 2010, 5:e12532.

21.

Wakabayashi Y, Inoue J, Takahashi Y, Matsuki A, Kosugi-Okano H, Shinbo T, Mishima Y, Niwa O, Kominami R: Homozygous deletions and point mutations of the Rit1/Bcl11b gene in gamma-ray induced mouse thymic lymphomas. Biochem Biophys Res Commun. 2003, 301: 598-603. 10.1016/S0006-291X(02)03069-3.CrossRefPubMed

22.

Kamimura K, Ohi H, Kubota T, Okazuka K, Yoshikai Y, Wakabayashi Y, Aoyagi Y, Mishima Y, Kominami R: Haploinsufficiency of Bcl11b for suppression of lymphomagenesis and thymocyte development. Biochem Biophys Res Commun. 2007, 355: 538-542. 10.1016/j.bbrc.2007.02.003.CrossRefPubMed

23.

MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG: Activation of HOX11L2 by juxtaposition with 3′-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). Genes Chromosomes Cancer. 2003, 37: 84-91. 10.1002/gcc.10194.CrossRefPubMed

24.

Przybylski GK, Dik WA, Wanzeck J, Grabarczyk P, Majunke S, Martin-Subero JI, Siebert R, Dolken G, Ludwig WD, Verhaaf B, van Dongen JJ, Schmidt CA, Langerak AW: Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL. Leukemia. 2005, 19: 201-208. 10.1038/sj.leu.2403619.CrossRefPubMed

25.

Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ: The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood. 2001, 98: 3413-3420. 10.1182/blood.V98.12.3413.CrossRefPubMed

26.

Bezrookove V, van Zelderen-Bhola SL, Brink A, Szuhai K, Raap AK, Barge R, Beverstock GC, Rosenberg C: A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene. Cancer Genet Cytogenet. 2004, 149: 72-76. 10.1016/S0165-4608(03)00302-9.CrossRefPubMed

27.

Oliveira JL, Kumar R, Khan SP, Law ME, Erickson-Johnson M, Oliveira AM, Ketterling RP, Dogan A: Successful treatment of a child with T/myeloid acute bilineal leukemia associated with TLX3/BCL11B fusion and 9q deletion. Pediatr Blood Cancer. 2011, 56: 467-469. 10.1002/pbc.22850.CrossRefPubMed

28.

Abbas S, Sanders M, Zeilemaker A, Geertsma-Kleinekoort WM, Koenders JE, Kavelaars FG, Abbas ZG, Mahamoud S, Chu IW, Hoogenboezem R, Peeters JK, van Drunen E, van Galen J, Beverloo HB, Löwenberg B, Valk PJ: Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations. Haematologica. 2014, 99: 848-57. 10.3324/haematol.2013.095604.PubMedCentralCrossRefPubMed

29.

De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van VP, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cavé H, Dastugue N, Raimondi S: The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med. 2010, 16: 1321-1327. 10.1038/nm.2246.PubMedCentralCrossRefPubMed

30.

Gutierrez A, Kentsis A, Sanda T, Holmfeldt L, Chen SC, Zhang J, Protopopov A, Chin L, Dahlberg SE, Neuberg DS, Silverman LB, Winter SS, Hunger SP, Sallan SE, Zha S, Alt FW, Downing JR, Mullighan CG, Look AT: The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood. 2011, 118: 4169-4173. 10.1182/blood-2010-11-318873.PubMedCentralCrossRefPubMed

31.

De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, Gianfelici V, Geerdens E, Clappier E, Porcu M, Lahortiga I, Lucà R, Yan J, Hulselmans G, Vranckx H, Vandepoel R, Sweron B, Jacobs K, Mentens N, Wlodarska I, Cauwelier B, Cloos J, Soulier J, Uyttebroeck A, Bagni C, Hassan BA, Vandenberghe P, Johnson AW, Aerts S, Cools J: Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet. 2013, 45: 186-190. 10.1038/ng.2508.CrossRefPubMed

32.

Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, Hadler M, Paietta E, Tallman MS, Rowe JM, Forne C, Rue M, Ferrando AA: Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood. 2013, 122: 74-82. 10.1182/blood-2013-03-491092.PubMedCentralCrossRefPubMed

33.

Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, De VJ, Hernandez JM, Hofmann WK, Mills KI, Gilkes A, Chiaretti S, Shurtleff SA, Kipps TJ, Rassenti LZ, Yeoh AE, Papenhausen PR, Liu WM, Williams PM, Foà R: Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the international microarray innovations in leukemia study group. J Clin Oncol. 2010, 28: 2529-2537. 10.1200/JCO.2009.23.4732.CrossRefPubMed

34.

Baldus CD, Martus P, Burmeister T, Schwartz S, Gokbuget N, Bloomfield CD, Hoelzer D, Thiel E, Hofmann WK: Low ERG and BAALC expression identifies a new subgroup of adult acute T-lymphoblastic leukemia with a highly favorable outcome. J Clin Oncol. 2007, 25: 3739-3745. 10.1200/JCO.2007.11.5253.CrossRefPubMed

35.

Heesch S, Schlee C, Neumann M, Stroux A, Kuhnl A, Schwartz S, Haferlach T, Goekbuget N, Hoelzer D, Thiel E, Hofmann WK, Baldus CD: BAALC-associated gene expression profiles define IGFBP7 as a novel molecular marker in acute leukemia. Leukemia. 2010, 24: 1429-1436. 10.1038/leu.2010.130.CrossRefPubMed

36.

Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM, Civin CI: STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994, 91: 459-463. 10.1073/pnas.91.2.459.PubMedCentralCrossRefPubMed

37.

Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME, Habib N, Yosef N, Chang CY, Shay T, Frampton GM, Drake AC, Leskov I, Nilsson B, Preffer F, Dombkowski D, Evans JW, Liefeld T, Smutko JS, Chen J, Friedman N, Young RA, Golub TR, Regev A, Ebert BL: Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell. 2011, 144: 296-309. 10.1016/j.cell.2011.01.004.PubMedCentralCrossRefPubMed

38.

Menssen HD, Renkl HJ, Rodeck U, Maurer J, Notter M, Schwartz S, Reinhardt R, Thiel E: Presence of Wilms' tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia. 1995, 9: 1060-1067.PubMed

39.

Rothenberg EV: Transcriptional drivers of the T-cell lineage program. Curr Opin Immunol. 2012, 24: 132-138. 10.1016/j.coi.2011.12.012.PubMedCentralCrossRefPubMed

40.

Li L, Leid M, Rothenberg EV: An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science. 2010, 329: 89-93. 10.1126/science.1188989.PubMedCentralCrossRefPubMed

41.

Koch U, Radtke F: Notch in T-ALL: new players in a complex disease. Trends Immunol. 2011, 32: 434-442. 10.1016/j.it.2011.06.005.CrossRefPubMed

42.

Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004, 306: 269-271. 10.1126/science.1102160.CrossRefPubMed

43.

Van VP, Ferrando A: The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest. 2012, 122: 3398-3406. 10.1172/JCI61269.CrossRef

44.

Kikuchi A, Hayashi Y, Kobayashi S, Hanada R, Moriwaki K, Yamamoto K, Fujimoto J, Kaneko Y, Yamamori S: Clinical significance of TAL1 gene alteration in childhood T-cell acute lymphoblastic leukemia and lymphoma. Leukemia. 1993, 7: 933-938.PubMed

45.

Bergeron J, Clappier E, Radford I, Buzyn A, Millien C, Soler G, Ballerini P, Thomas X, Soulier J, Dombret H, Macintyre EA, Asnafi V: Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood. 2007, 110: 2324-2330. 10.1182/blood-2007-04-079988.CrossRefPubMed

46.

Kraszewska MD, Dawidowska M, Kosmalska M, Sedek L, Grzeszczak W, Kowalczyk JR, Szczepanski T, Witt M: BCL11B, FLT3, NOTCH1 and FBXW7 mutation status in T-cell acute lymphoblastic leukemia patients. Blood Cells Mol Dis. 2013, 50: 33-38. 10.1016/j.bcmd.2012.09.001.CrossRefPubMed

47.

Kurosawa N, Fujimoto R, Ozawa T, Itoyama T, Sadamori N, Isobe M: Reduced level of the BCL11B protein is associated with adult T-cell leukemia/lymphoma.PLoS One 2013, 8:e55147.

48.

Brüggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, Luschen S, Pott C, Ritgen M, Scheuring U, Horst HA, Thiel E, Hoelzer D, Bartram CR, Kneba M: Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006, 107: 1116-1123. 10.1182/blood-2005-07-2708.CrossRefPubMed

49.

Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M, Burmeister T, Schwartz S, Bloomfield CD, Hoelzer D, Thiel E, Hofmann WK: Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica. 2009, 94: 1383-1390. 10.3324/haematol.2008.005272.PubMedCentralCrossRefPubMed

50.

Gokbuget N, Raff R, Brüggemann M, Flohr T, Scheuring U, Pfeifer H, Bartram CR, Kneba M, Hoelzer D: Risk/MRD adapted GMALL trials in adult ALL. Ann Hematol. 2004, 83 (Suppl 1): S129-S131.PubMed

51.

European leukemia Net. European leukemia trial registry trial: ALL GMALL 07/2003.. Accessed September 3, 2013. ., [http://www.leukemia-net.org/trial/download/public/ALL_GMALL07-03_ShortProtEN.pdf?id=489]

52.

Baldus CD, Burmeister T, Martus P, Schwartz S, Gokbuget N, Bloomfield CD, Hoelzer D, Thiel E, Hofmann WK: High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults. J Clin Oncol. 2006, 24: 4714-4720. 10.1200/JCO.2006.06.1580.CrossRefPubMed

53.

Heesch S, Goekbuget N, Stroux A, Tanchez JO, Schlee C, Burmeister T, Schwartz S, Blau O, Keilholz U, Busse A, Hoelzer D, Thiel E, Hofmann WK, Baldus CD: Prognostic implications of mutations and expression of the Wilms tumor 1 (WT1) gene in adult acute T-lymphoblastic leukemia. Haematologica. 2010, 95: 942-949. 10.3324/haematol.2009.016386.PubMedCentralCrossRefPubMed

54.

Neumann M, Coskun E, Fransecky L, Mochmann LH, Bartram I, Sartangi NF, Heesch S, Gokbuget N, Schwartz S, Brandts C, Schlee C, Haas R, Dührsen U, Griesshammer M, Döhner H, Ehninger G, Burmeister T, Blau O, Thiel E, Hoelzer D, Hofmann WK, Baldus CD: FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors.PLoS One 2013, 8:e53190.

Title: Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients
Authors: Isabelle Bartram
Nicola Gökbuget
Cornelia Schlee
Sandra Heesch
Lars Fransecky
Stefan Schwartz
Reingard Stuhlmann
Kerstin Schäfer-Eckhart
Michael Starck
Albrecht Reichle
Dieter Hoelzer
Claudia D Baldus
Martin Neumann
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2014
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-014-0051-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice

Toll-like receptors in the pathogenesis of human B cell malignancies

DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells

Catechins induced acute promyelocytic leukemia cell apoptosis and triggered PML-RARα oncoprotein degradation

Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma

Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein

Keynote webinar | Spotlight on antibody–drug conjugates in cancer