Hematolymphoid Tumors

 

Principal Investigators

 

Prof. Dr. Stefan Dirnhofer

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Prof. Dr. Alexandar Tzankov

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Group Members

 

Visar Vela

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Dr. Darius Juškevičius

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PD Dr. Thomas Menter

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Dr. Magdalena Brune

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Our Science

 


Our hematopathology research group focuses on translational investigations and precision medicine of lymphomas. We have assembled a team of scientists to advance knowledge in the following distinct topics:

 

Clonal relationships and molecular evolution of relapsing lymphomas

A major research topic of our group is deciphering the clonal relationship and evolution of recurrent lymphomas. Relapses of lymphoid neoplasms, even after long-lasting clinical remission, were regarded until recently as direct outgrowths of the primary tumor. Only rarely clonally unrelated relapses have been documented as single case reports. We hypothesized that clonally unrelated (true “de novo”) cases of “relapsing” lymphomas are more common than generally thought. By comparative immunoglobulin heavy chain-gene fragment length analysis of microdissected Reed-Sternberg cells from matched primary and relapsing classic Hodgkin lymphoma (HL) samples, we could demonstrate that a proportion of recurrences are clonally unrelated and, therefore, not true “relapses” of the original malignant clone (Clin Cancer Res. 2011;17:5268-5274). This may be of clinical significance because it raises the questions about the current aggressive clinical therapies in such instances (Figure 1).

We then extended the hypothesis of clonally unrelated relapses to diffuse large B-cell lymphomas (DLBCL). A cohort of paired relapsing DLBCL- and non-relapsing cases has been extensively studied (Leukemia 2016;30:2385-2395). We were able to demonstrate that true clonally unrelated DLBCL-recurrences do also occur. We could identify two distinct patterns of genetic evolution in clonally related relapses (early divergent/branching evolution versus late-divergent/linear progression) and potential early mutational drivers of lymphomagenesis (e.g., KMT2D, MYD88, CD79B), some of which are now used to predict sensitivity towards ibrutinib. In addition, we were able to detect mutations of distinct genes that were either linked to relapses (BCL2, MEF2B) or predicted lesser propensity for recurrences (SOCS1). Along this project, a next generation sequencing (NGS) panel for lymphomas has been developed in our lab that entered clinical routine after validation (Leuk Lymphoma 2018;59:1710-1716) and accreditation and is still the only one running in a diagnostic lab in Europe (https://www.unibas.ch/en/Research/Uni-Nova/Uni-Nova-128/Uni-Nova-128-New-treatment-concepts-for-recurrent-lymphoma.html). To address these issues at the single gene level in HL, we established a novel cell enrichment technique for robust genetic analysis of Reed-Sternberg cells (Lab Invest. 2018;98:1487-1499) and are currently running a respective project.

Figure 1: Concepts of lymphoma recurrences.
Upper row: 10 to 20% of clinical lymphoma relapses, i.e. same tumor entity occurring at two different time points, are clonally unrelated second tumors. The remaining are clonally related and show at least two different molecular evolution patterns. Middle row: In the linear evolution scenario, the tumor initially possesses a strong driver mutations. Therefore, the neoplastic cells grow fast and unrestricted, giving rise to a rather homogeneous primary tumor. Such a tumor is almost exterminated by the treatment but an acquired resistance emerges. The resistant subclone already has drivers of effective growth and replenishes the tumor mass giving rise to a more rapid relapse. Lower row: In the branching scenario, the divergence occurs early in tumor development. The majority of subpopulations stagnate but one clone eventually acquires the effective combination of driver mutations, expands and gives rise to a heterogeneous primary tumor. The dominant population is exterminated by the treatment, however, an intrinsically resistant subclone exists and gradually gives rise to a relapse
 

Deciphering the genetic landscape of marginal zone lymphomas

Figure 2. Nodal marginal zone lymphoma expressing V600E mutant BRAF
One significant discovery of ours is the detection of a recurrent mutation in BRAF gene in about 15% of marginal zone B cell lymphomas. This mutation is useful in that the mutated protein product can be visualized using simple staining methods as illustrated and is, therefore, diagnostically applicable, and the mutated protein product can be specifically targeted, at least in other types of cancer such as melanoma or hairy cell leukemia.

We decided to apply and extend this NGS panel towards more orphan lymphomas, namely marginal zone lymphomas (MZL). These are rare lymphoid tumors comprising three different, but morphologically and phenotypically closely related entities (splenic, nodal and extranodal MZL). Nodal MZL is a diagnosis of exclusion as defined by the current WHO-classification, has no disease-defining phenotype and its diagnostic borders to other B-cell lymphomas are blurred. By studying 25 nodal MZL, we identified for the first time recurrent and diagnostically useful BRAF-mutations, mainly V600E (Leukemia. 2018;32:2412-26; Figure 2). Most importantly, the V600E mutation of this gene is therapeutically relevant since a targeted treatment for this molecular alteration is approved in melanoma and relapsing hairy cell leukemia. We further extended our studies on MZL to ocular adnexal (OA) MZL. Preliminary data shows that TNFAIP3 mutations are highly specific and BCL10 mutations are probably prognostically important in OA MZL, and that OA lymphoid lesions bearing NF-κB compound mutations and/or mutations of acetyltransferase-encoding genes highly likely represent lymphomas (Der Pathologe 2019;40 Suppl. 2:S109-10). Finally, in MZL of the lung, we were able to detect higher frequency of cases without point mutations suggesting that these malignancies are more translocation-driven, and showed that – based on the dissimilar mutational profile between the two entities – DLBCL and MZL of the lung are unrelated (Modern Pathology. 2020; in press).

 

Selected Publications

2020

  • Gerlach MM, Juskevicius D, Vela V, Dirnhofer S, Tzankov A. Bone marrow infiltration of angioimmunoblastic T-cell lymphoma: identification and prognostic impact of histological patterns and diagnostic application of ancillary phenotypic and molecular analyses; Archives of Pathology and Laboratory Medicine. 2020 144:602-611.
  • Gerlach MM, Stelling-Germani A, Wu CT, Newrzela S, Döring C, Vela V, Müller A, Hartmann S, Tzankov A. SMAD1 promoter hypermethylation and lack of SMAD1 expression in Hodgkin Lymphoma: A potential target for hypomethylating drug therapy; Haematologica. 2020, Apr 16.
  • Menter T, Tzankov A, Zucca E, Kimby E, Hultdin M, Sundström C, Beiske K, Cogliatti S, Banz Y, Cathomas G, Karjalainen-Lindsberg ML, Grobholz R, Mazzucchelli L, Sander B, Hawle H, Hayoz S, Dirnhofer S for the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG). Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy; British Journal of Haematology. 2020 189:707-717.
  • Menter T, Hayoz S, Zucca E, Kimby E, Dirnhofer S, Tzankov A. Immunomodulatory drugs may overcome the negative prognostic role of active Th17 axis in follicular lymphoma: evidence from the SAKK35/10 trial; British Journal of Haematology. 2020 190, e233–e264.
  • Pillonel V, Juskevicius D, Bihl M, Stenner F, Halter JP, Dirnhofer S, Tzankov ARoutine next generation sequencing of lymphoid malignancies: clinical utility and challenges from a 3-year practical experience; Leukemia and Lymphoma. 2020, Jul 4;1-16.
  • Vela V, Juskevicius D, Gerlach MM, Meyer P, Graber A, Cathomas G, Dirnhofer S, Tzankov A. High throughput sequencing reveals high specificity of TNFAIP3 mutations in ocular adnexal marginal zone B-cell lymphomas; Hematological Oncology. 2020 38:284-292.
  • Vela V, Juskevicius D, Savic Prince S, Cathomas G, Dertinger S, Diebold J, Bubendorf L, Horcic M, Singer G, Zettl A, Dirnhofer S, Tzankov A* and Menter T*Deciphering the genetic landscape of pulmonary lymphomas; Modern Pathology. 2020 Aug 27.

 

Earlier

  • Cascione L, Rinaldi A, Bruscaggin A, Tarantelli C, Arribas AJ, Kwee I, Pecciarini L, Mensah AA, Spina V, Chung EYL, Terzi di Bergamo L, Dirnhofer S, Tzankov A, Miranda RN, Young KH, Traverse-Glehen A, Gaidano G, Swerdlow SH, Gascoyne R, Rabadan R, Ponzoni M, Bhagat G, Rossi D, Zucca E, Bertoni F. Novel insights in the genetics and epigenetics of MALT lymphoma unveiled by next generation sequencing analyses; Haematologica. 2019 104:e558-e561
  • Menter T, Lundberg P, Wenzel F, Dirks J, Fernandez P, Friess D, Dirnhofer S, Tzankov A. RUNX1 mutations can lead to aberrant expression of CD79a and PAX5 in acute myelogenous leukemias: a potential diagnostic pitfall; Pathobiology. 2019 86:162-166
  • Hashwah H, Bertram K, Stirm K, Stelling A, Wu CT, Kasser S, Manz MG, Theocharides PA, Tzankov A, Müller AThe IL-6 signaling complex is a critical driver, negative prognostic factor and therapeutic target in diffuse large B-cell lymphoma; European Molecular Biology Organization Molecular Medicine. 2019 11:e10576
  • Juskevicius D, Jucker D, Dietsche T, Perrina V, Rufle A, Ruiz C, Dirnhofer S, Tzankov ANovel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues; Laboratory Investigation. 2018 98:1487-1499
  • Juskevicius D, Müller A, Hashwah H, Lundberg P, Tzankov A, Menter T. Characterization of the mutational profile of 11 diffuse large B-cell lymphoma cell lines; Leukemia and Lymphoma. 2018 59:1710-1716
  • Menter T, Juskevicius D, Alikian M, Steiger J, Dirnhofer S, Tzankov A* and Naresh KN*. Mutational landscape of B-cell post-transplant lymphoproliferative disorders; British Journal of Haematology. 2017 178:48-56
  • Juskevicius D, Jucker D, Klingbiel D, Mamot C, Dirnhofer S, Tzankov A. Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B-cell lymphoma: Mutational analysis of the SAKK 38/07 prospective clinical trial cohort; Journal of Hematology & Oncology. 2017 10:70
  • Xia* Y, Xu-Monette* ZY and Tzankov* A, Manyam GC, Pasqualucci L, Zhang L, Murty V, Visco C, Dybkaer K, Bhagat G, Chiu A, Orazi A, Zu Y, Richards KL, His ED, Choi WWL, van Krieken JH, Huh J, Ponzoni M, Ferreri AJM, Møller MB, Parsons BM, Winter JN, Piris MA, Li J, Dalla-Favera R, Medeiros LJ, Young KH. Loss of PRDM1/BLIMP-1 function contributes to the poor prognosis of activated B cell-like diffuse large B cell lymphoma; Leukemia. 2017 31:625-636
  • Juskevicius D, Lorber T, Gsponer J, Perrina V, Ruiz C, Stenner-Liewen F, Dirnhofer S, Tzankov ADistinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome wide copy number aberration and targeted sequencing analysis; Leukemia. 2016 30:2385-2395
  • Menter T, Bodmer-Haecki A, Dirnhofer S, Tzankov AEvaluation of the diagnostic and prognostic value of PDL1-expression in Hodgkin- and B-cell lymphomas; Human Pathology. 2016 57:17-24
  • Medinger M, Krenger W, Jakab A, Bucher C, Passweg J, Tzankov A. Numerical impairment of nestin+ bone marrow niches in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia; Bone Marrow Transplantation. 2015 50:1453-1458
  • Tzankov A, Leu N, Muenst S, Juskevicius D, Klingbiel D, Mamot C, Dirnhofer SMultiparameter analysis of homogeneously R-CHOP treated diffuse large B-cell lymphomas identifies CD5 and FOXP1 as relevant prognostic biomarkers: report of the prospective SAKK 38/07 study; Journal of Hematology & Oncology. 2015 8:70
  • Tzankov A, Xu-Monette ZY, Gerhard M, Visco C, Dirnhofer S, Gisin N, Dybkaer K, Orazi A, Bhagat G, Richards KL, His ED, Choi WWL, van Krieken JH, Ponzoni M, Ferreri AJM, Winter JN, Go RS, Piris MA, Møller MB, You MJ, McDonnell T, Medeiros LJ, Young KH. Rearrangements of MYC Gene facilitate risk stratification in diffuse large-B cell lymphoma patients treated with Rituximab-CHOP; Modern Pathology. 2014 27:958-971
  • Arranz L, Sánchez-Aguilera A, Martín-Pérez D, Isern J, Langa X, Tzankov A, Lundberg P, Schwaller J, Skoda RC, Méndez-Ferrer S. Sympathetic neuropathy of blood stem cell niche is essential for myeloproliferative neoplasms; Nature. 2014 512:78-81

 *equal contributions