scholarly journals Examining the Role of CD30 in an Anaplastic Large Cell Lymphoma Mouse Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2542-2542
Author(s):  
Teresa Poggio ◽  
Linda Graessel ◽  
Stefanie Kreutmair ◽  
Cornelius Miething ◽  
Dietmar Pfeifer ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Disease Development ◽  
Large Cell Lymphoma ◽  
The Impact

Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of T-cell non-Hodgkin lymphoma (NHL) mainly affecting children and young adults. About 70% of systemic ALCLs are associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in the NPM-ALK fusion gene, its over-expression and constitutive kinase activity. Immunophenotypic characterization of human ALCL revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on disease development remains unclear and the relationship between NPM-ALK and CD30 has been investigated mostly using cell line models. Syngeneic mouse models of cancer can serve as useful models since the tumors develop in situ where the contribution made by the immune system and the extracellular matrix can be investigated. Here, we focus on the involvement of CD30 in a retroviral murine bone marrow transplantation model of ALCL. In this model, the BM of Lck-Cre-transgenic mice is infected with a MSCV-Stop-NPM-ALK-IRES-EGFP vector leading to expression of NPM-ALK in early T-cells. With a latency of 3-4 months, mice develop lymphomas and die from neoplastic T-cell-infiltration of BM and lymphatic organs. To investigate the impact of abrogation of CD30 signals on the development of NPM-ALK+ ALCL in our model, CD30 knockout mice were crossed with Lck-Cre mice. Both Lck-Cre NPM-ALK CD30 wt and Lck-Cre NPM-ALK CD30 ko recipients develop a human ALCL-like lymphoma with a pure T-cell phenotype characterized by Thy1.2+ cells infiltrating the thymus, lymph nodes, spleen and BM. First results from Lck-Cre NPM-ALK CD30 ko transplanted mice showed impaired disease induction and prolonged survival compared to CD30 wt animals. Moreover, secondary transplantation of NPM-ALK thymic lymphomas led to distinct deceleration of disease development upon CD30 deletion. Microarray analyses have shed some light on the mechanisms underlying the delayed lymphoma progression of CD30 deleted tumors with an upregulation of inflammatory pathways and proteins that are master players in inflammation and immune responses. Further characterization of the role of CD30-mediated immune response in disease progression using this mouse model and immunocompromised mice is ongoing. An improved understanding of how the immune system affects tumor progression will extend the rationale in translational strategies to use immunotherapies for patients with T-NHLs. Disclosures No relevant conflicts of interest to declare.

The Role of IgM Antibodies in T Cell Lymphoma Protection in a Novel Model Resembling Anaplastic Large Cell Lymphoma

2021 ◽  
pp. ji2001279
Author(s):  
Chuancang Jiang ◽  
Ming-Lang Zhao ◽  
Luis Ramos ◽  
Katarzyna Dobaczewska ◽  
Ronald Herbert ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Igm Antibodies ◽  
Large Cell Lymphoma ◽  
Novel Model

scholarly journals IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 360-370 ◽  
Author(s):  
Ping Shi ◽  
Raymond Lai ◽  
Quan Lin ◽  
Abid S. Iqbal ◽  
Leah C. Young ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Malignant Lymphoma ◽  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Type I ◽  
Large Cell Lymphoma

Abstract Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK+ ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK+ ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK+ ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK+ ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK+ ALCL and possibly other types of malignant lymphoma.

Generation and Characterization Of a CD30 Positive T-Cell Lymphoma Mouse Model Resembling Human Anaplastic Large Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2450-2450
Author(s):  
Cathrin Klingeberg ◽  
Anna Lena Illert ◽  
Nicolas Schneider ◽  
Christian Peschel ◽  
Cornelius Miething ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Large Cell ◽  
Cre Recombinase ◽  
Double Negative ◽  
Ki 67 ◽  
The Impact

Abstract Anaplastic large cell lymphomas (ALCL) are a subgroup of aggressive Non-Hodgkin-Lymphomas mainly affecting children and young adults. In 60 % of systemic ALCLs, a translocation t(2;5) (p23;q35) resulting in NPM-ALK fusion gene expression is found. The constitutively activation of ALK tyrosine kinase expressed from the NPM-promoter causes increased proliferation and inhibition of apoptosis thereby promoting cell survival and tumorigenesis. Immunphenotypic characterization of human ALCLs revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on diseases development as well as NPM-ALK signal transduction in course of disease remains unclear and appropriate mouse models to answer these questions are missing. In this regard, we established a retroviral murine bone marrow (BM) transplantation model resembling a human ALCL-like T-cell neoplasia. Therefore we use an inducible Cre/loxP system where NPM-ALK expression is controlled and expressed in a special type of early T-cells. For generation of this vector, we inserted a floxed translational ‘stop-cassette’ between the retroviral promoter MSCV-LTR and the NPM-ALK cDNA, which guaranties specific expression of NPM-ALK only in cells, where the enzyme Cre-recombinase is expressed. Recognition of the loxP-sites by Cre-recombinase leads in our system to deletion of the stop-cassette and consequently NPM-ALK expression. Using different Cre-expressing cell types allowed us to study pathogenesis of ALCL in more detail. In our recent study, we infected bone marrow of transgenic mice expressing Cre-recombinase under the control of the Lck-promotor with our MSCV-Stop-NPM-ALK-IRES-EGFP (MSNAIE) vector and transplanted it into lethally irradiated C57Bl6 recipient mice. With a latency of 4-5 months, these mice developed Thy1.2-positive lymphomas and died from neoplastic infiltration of bone marrow and lymphatic organs with T-cells. Immunphenotypic analyses confirmed T-Cell origin of the lymphomas and showed importantly highly CD30-expression. Staining of the different T-cell-subpopulations demonstrated highest NPM-ALK expression in immature CD4/CD8 double negative T-cells and not fully differentiated CD4/CD8 double positive T-cells. Interestingly, FACS-staining of the proliferation marker Ki-67 revealed highest expression in CD4/CD8 double negative T-cells, in contrast to the other subpopulations where Ki-67 is less detected. Therefore we hypothesized, that the lymphoma initiating cell (LIC) must be within this early T-cell population. Most interestingly we found highest CD30-expression just in the same CD4/CD8 negative T-cell population, pointing to a crucial role of CD30 in lymphoma initiation. To further substantiate our hypothesis we performed secondary and tertiary transplantations with different sorted T-Cell subpopulation and indeed, the immature CD4/CD8 double negative population was able to initiate lymphoma growth in recipient mice. Further transplantations by limited dilution will help to identify the leukemia initiating cell in this model. Taken together, our murine LckCre-NPM-ALK bone marrow transplantation model represents a precise and versatile tool to study disease initiation and development resembling human ALCL. Moreover, the impact of specific proteins (e.g. CD30) in the course of disease can be addressed by combining Knockout (e.g. CD30)/LckCre transgenic mice with our model. To this end we crossed CD30/Lck-Cre mice, and preliminary analysis indicate that CD30 expression seems not to be required for the initial onset of disease. Further characterization of the role of CD30 in ALCL is ongoing. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Breast implant-associated, ALK-negative, T-cell, anaplastic, large-cell lymphoma: Establishment and characterization of a model cell line (TLBR-1) for this newly emerging clinical entity

Cancer ◽  
2010 ◽  
Vol 117 (7) ◽  
pp. 1478-1489 ◽  
Author(s):  
Melissa G. Lechner ◽  
Stephen Lade ◽  
Daniel J. Liebertz ◽  
H. Miles Prince ◽  
Garry S. Brody ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Breast Implant ◽  
Large Cell ◽  
Clinical Entity ◽  
Model Cell ◽  
Large Cell Lymphoma

scholarly journals 51 Small cell/lymphohistiocytic morphology is associated with CD8 positivity, retained T cell markers, a trend of decreased PD-L1 expression, but not outcome in adults with ALK+ ALCL

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A54-A54
Author(s):  
Mahsa Khanlari ◽  
Shaoying Li ◽  
Roberto N Miranda ◽  
Swaminathan Iyer ◽  
Cameron Yin ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Small Cell ◽  
Adult Patients ◽  
World Health ◽  
Proliferation Index ◽  
Cell Markers ◽  
Large Cell Lymphoma

BackgroundSeveral morphologic patterns of ALK+ anaplastic large cell lymphoma (ALCL) are recognized: common, small cell, lymphohistiocytic, Hodgkin-like, and composite patterns.1 Small cell (SC) and lymphohistiocytic (LH) patterns are thought to be closely associated with poorer outcome in children with ALK+ ALCL.2 However, the clinicopathologic and prognostic features of SC/LH patterns of ALK+ ALCL are not yet reported in adults. Recently, we found PD-L1 expression in a large subset of ALK+ ALCL cases, however, PD-L1 expression in SC/LH versus non-SC/LH ALCL has not been reported.MethodsAmong 102 adult patients with ALK+ ALCL seen at our institution from January 1, 2007 through August 30, 2018, 18 (18%) cases had a SC and/or LH pattern. The clinical, pathologic, and outcome data were compared between SC/LH and non-SC/LH ALK+ ALCL cases using Fisher’s exact test. Overall survival (OS) was analyzed using the Kaplan-Meier method and compared using the log-rank test.ResultsThere were no significant differences in clinical features including age, gender, nodal versus extranodal involvement, B symptoms, stage, leukocytosis/lymphocytosis, and serum LDH levels between patients with SC/LH versus non-SC/LH ALK+ ALCL. Compared to non-SC/LH cases, SC/LH ALCL was more often positive for CD2 (92% vs. 36%, p = 0.0007), CD3 (81% vs. 15%, p = 0.0001), CD7 (80% vs. 37%, p = 0.03), and CD8 (54% vs. 7%, p = 0.0006). SC/LH ALCL showed a trend of decreased PD-L1 expression than non-SC/LH cases (24% vs. 46%, p = 0.11). There were no significant differences in the expression of CD4, CD5, CD25, CD43, CD45, CD56, TCR A/B, TCR G/D, cytotoxic markers, EMA, Ki-67 proliferation index. The induction chemotherapy and response rate in patients with SC/LH ALK+ ALCL were similar to patients with non-SC/LH ALK+ ALCL. After a median follow-up of 30.5 months (range, 0.3–224 months), there was no significant difference in OS between patients with SC/LH versus non-SC/LH ALK+ ALCL (p = 0.88).ConclusionsIn adults with ALK+ALCL, the SC/LH morphologic pattern is associated with a CD8+ T cell immunophenotype and retention of expression of T cell markers (CD2, CD3, and CD7). The trend of decreased PD-L1 expression in SC/LH ALCL suggests that these patients may not be ideal candidates for PD-L1 immunotherapy. The SC/LH patterns of ALK+ ALCL have no impact on the prognosis of adult patients which is in contrast to the reported association of the SC/LH patterns with poorer outcome in children with ALK+ ALCL.Ethics ApprovalThe study was approved by the Institutional Review Board at MD Anderson Cancer Center, Approval number: PA16-0897ReferencesSwerdlow SH, Campo E, The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375–2390.Brugières L, Deley MC, CD30 (+) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 1998;92:3591–3598.

Primary Cutaneous CD30-Positive Anaplastic Large Cell Lymphoma in Childhood: Report of 4 Cases and Review of the Literature

2005 ◽  
Vol 8 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Shimareet Kumar ◽  
Stefania Pittaluga ◽  
Mark Raffeld ◽  
Michael Guerrera ◽  
Nita L. Seibel ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Subcutaneous Tissue ◽  
Pediatric Population ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Cell Phenotype ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

We present the clinicopathologic findings in 4 children with primary cutaneous anaplastic large cell lymphoma (C-ALCL). The patients ranged in age from 13 months to 8 years, with 3 females and 1 male. All presented with a rapidly enlarging mass involving the skin and subcutaneous tissue. Histologic evaluation showed sheets of large pleomorphic lymphoid cells that were diffusely and strongly CD30+. Tumor cells were CD45+ in 1 of 4 cases. Cells were of T-cell phenotype, with variable positivity for CD3 (3 of 4 cases) and CD5 (2 of 4 cases). All 4 cases were positive for CD4 and clusterin. Staining for anaplastic lymphoma kinase was negative in all cases. No evidence of systemic involvement was noted at initial presentation or over a follow-up of 5 to 78 months, although 3 patients had cutaneous recurrences. Primary C-ALCL has only rarely been described in the pediatric population. The high-grade histologic appearance of this lymphoma belies its generally favorable clinical course and prognosis. Recognition of this entity and its differentiation from other T-cell lymphomas that secondarily involve the skin is important to avoid unnecessarily aggressive therapy in these children.

Anaplastic Large Cell Lymphoma Arising in Bone

2000 ◽  
Vol 124 (9) ◽  
pp. 1339-1343
Author(s):  
Mark A. Lones ◽  
Warren Sanger ◽  
Sherrie L. Perkins ◽  
L. Jeffrey Medeiros
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Correct Diagnosis ◽  
Cell Lineage ◽  
Antigen Expression ◽  
Large Cell ◽  
Null Cell ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Abstract Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

Angiotropic (Intravascular) Large Cell Lymphoma of T-Cell Phenotype Presenting as Acute Appendicitis in a Patient With Acquired Immunodeficiency Syndrome

1999 ◽  
Vol 123 (4) ◽  
pp. 335-337 ◽  
Author(s):  
Denise M. Malicki ◽  
Yae K. Suh ◽  
Gregory N. Fuller ◽  
Sung S. Shin
Keyword(s):  
T Cell ◽  
Acute Appendicitis ◽  
Acquired Immunodeficiency Syndrome ◽  
Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Large Cell ◽  
Cell Phenotype ◽  
Acquired Immunodeficiency ◽  
Large Cell Lymphoma ◽  
Immunodeficiency Syndrome

Abstract We describe a patient with acquired immunodeficiency syndrome who presented with acute appendicitis but was found to have angiotropic large cell lymphoma (ALCL) by pathologic examination of the appendectomy specimen, without acute inflammation. Very rare cases of angiotropic large cell lymphoma have been reported in patients with human immunodeficiency virus infection, and most cases of this rare lymphoma are of B-cell origin, but in this instance immunohistochemical analysis showed a T-cell phenotype.

scholarly journals How I treat breast implant–associated anaplastic large cell lymphoma

Blood ◽  
2018 ◽  
Vol 132 (18) ◽  
pp. 1889-1898 ◽  
Author(s):  
Neha Mehta-Shah ◽  
Mark W. Clemens ◽  
Steven M. Horwitz
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Breast Implant ◽  
Large Cell ◽  
World Health ◽  
Team Approach ◽  
Textured Surface ◽  
Complete Surgical Excision ◽  
Large Cell Lymphoma

Abstract Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared with many other subtypes of systemic T-cell lymphoma; however, unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients. In this paper, we share our recommendations for a multidisciplinary team approach to the diagnosis, workup, and treatment of BIA-ALCL in line with consensus guidelines by the National Comprehensive Cancer Network.

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