Adult T Cell Leukemia/Lymphoma Development in HTLV-1-Infected Humanized SCID Mice.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1425-1425
Author(s):  
Prabal Banerjee ◽  
Michael D Lairmore ◽  
Juan Carlos Ramos ◽  
William J Harrington ◽  
Mark A Beilke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Animal Model ◽  
T Cell ◽  
Scid Mice ◽  
Cd4 T Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia

Abstract Abstract 1425 Poster Board I-448 Human T-lymphotropic virus type-1 (HTLV-1) is the first human retrovirus linked to cancer and is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+ T cell malignancy. The molecular and genetic factors induced by HTLV-1 that initiate ATLL remain unclear, in part, due to the lack of an animal model which recapitulates leukemogenic events. In particular, early target cell infection and transformation events have not been identified or defined. Herein, we have created humanized NOD/SCID (HU-NOD/SCID) mice by inoculation of NOD/SCID mice with CD34+ hematopoietic progenitor and stem cells (CD34+ HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice consistently developed CD4+ T cell lymphomas with characteristics similar to ATLL. Elevated proliferation of infected human stem cells (CD34+CD38−) in the bone marrow was observed in mice developing malignancies. Furthermore, examination of CD34+ HP/HSCs from HTLV-1-infected patients revealed proviral integrations suggesting a role of human bone marrow-derived stem cells in leukemogenesis. NOD/SCID mice reconstituted with CD34+ HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1 oncoprotein (Tax1) also developed CD4+ lymphomas. The recapitulation of a CD4+ T cell lymphoma in HTLV-1- and Tax1-HU-NOD/SCID mice suggest that hematopoietic stem cells serve as a viral reservoir in vivo and provide a cellular target for cell transformation in humans. This animal model of HTLV-1 induced ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Adult T-cell leukemia/lymphoma development in HTLV-1–infected humanized SCID mice

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2640-2648 ◽  
Author(s):  
Prabal Banerjee ◽  
Adam Tripp ◽  
Michael D. Lairmore ◽  
Lindsey Crawford ◽  
Michelle Sieburg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Animal Model ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Cd4 T Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

AbstractThe molecular and genetic factors induced by human T-lymphotropic virus type-1 (HTLV-1) that initiate adult T-cell leukemia/lymphoma (ATLL) remain unclear, in part from the lack of an animal model that accurately recapitulates leukemogenesis. HTLV-1–infected humanized nonobese diabetic severe combined immunodeficiency (HU-NOD/SCID) mice were generated by inoculation of NOD/SCID mice with CD34+ hematopoietic progenitor and stem cells (CD34+ HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice exclusively developed CD4+ T-cell lymphomas with characteristics similar to ATLL and elevated proliferation of infected human stem cells (CD34+CD38−) in the bone marrow were observed in mice developing malignancies. Purified CD34+ HP/HSCs from HTLV-1–infected patient peripheral blood mononuclear cells revealed proviral integrations suggesting viral infection of human bone marrow–derived stem cells. NOD/SCID mice reconstituted with CD34+ HP/HSCs transduced with a lentivirus vector expressing the HTLV-1 oncoprotein (Tax1) also developed CD4+ lymphomas. The recapitulation of a CD4+ T-cell lymphoma in HU-NOD/SCID mice suggests that HSCs provide a viral reservoir in vivo and act as cellular targets for cell transformation in humans. This animal model of ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Blood ◽  
2014 ◽  
Vol 123 (3) ◽  
pp. 346-355 ◽  
Author(s):  
Kenta Tezuka ◽  
Runze Xun ◽  
Mami Tei ◽  
Takaharu Ueno ◽  
Masakazu Tanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Animal Model ◽  
Immune Responses ◽  
Humanized Mice ◽  
Cell Leukemia ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Adaptive Immune ◽  
Key Points

Key Points Humanized mice, IBMI-huNOG, were generated by intra–bone marrow injection of human CD133+ hematopoietic stem cells. HTLV-1–infected IBMI-huNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1–specific adaptive immune responses.

scholarly journals A model of in vivo cell proliferation of adult T-cell leukemia

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2501-2509 ◽  
Author(s):  
A Kondo ◽  
K Imada ◽  
T Hattori ◽  
H Yamabe ◽  
T Tanaka ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Scid Mice ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Beta Chain ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract We have made a model of in vivo cell proliferation of leukemic cells from adult T-cell leukemia (ATL) patients using severe combined immunodeficiency (SCID) mice. Peripheral blood mononuclear cells (PBMC) or lymph node cells (LNC) depleted of B cells and monocytes were intraperitoneally injected into SCID mice treated with antimurine interleukin-2 receptor (IL-2+) beta chain monoclonal antibody (MoAb)(TM- beta 1), followed by daily injection of human recombinant IL-2 until 60 days after cell injection. SCID mice injected with ATL cells from 6 of 8 ATL patients were found to have the tumor or leukemia 5 to 7 weeks after the inoculation of cells. Serum levels of soluble form of human IL-2R alpha chain (Tac) were markedly elevated in such mice. The cells recovered from the mice injected with leukemic cells from four different ATL patients had the same cell surface phenotype as that of original leukemic cells which were CD4+Tac+. Furthermore, we detected the same integration site of human T-cell leukemia virus type I (HTLV- I) provirus and the same rearrangement pattern of human T-cell receptor (TCR) beta chain gene as those of ATL cells by Southern blot hybridization, indicating that the cells proliferating in SCID mice were derived from the original ATL cell clone. Histologic examination showed that the pattern of the infiltration of ATL cells into various organs in SCID mice was similar to that of an ATL patient. Such a model of in vivo cell proliferation of ATL cells will be useful for the study of the mechanism of neoplastic cell proliferation and for the development of a new and effective treatment of ATL.

Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID Mice Engrafted With Adult T-Cell Leukemia Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4747-4751 ◽  
Author(s):  
Akifumi Takaori-Kondo ◽  
Kazunori Imada ◽  
Itsuo Yamamoto ◽  
Akane Kunitomi ◽  
Yasuharu Numata ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
T Cell ◽  
Scid Mice ◽  
T Cell Leukemia ◽  
Related Protein ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Abstract Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

scholarly journals Pathologically Proven Intraocular Infiltration With Adult T-Cell Leukemia/Lymphoma: Two New Cases With Either Vitreous Opacity or Aqueous Hypopyon and Literature Review of 16 Cases

2020 ◽  
Vol 8 ◽  
pp. 232470962096684
Author(s):  
Toshihiko Matsuo ◽  
Takehiro Shimizu ◽  
Takehiro Tanaka ◽  
Akira Yamamoto ◽  
Hiroki Takasuka
Keyword(s):  
T Cell ◽  
Kidney Injury ◽  
Central Nervous System Relapse ◽  
Acute Type ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
First Case ◽  
Vitreous Opacity

This study reported 2 new patients and 16 historical cases with pathologically proven intraocular infiltration with adult T-cell leukemia and lymphoma (ATLL) to know the timing of intraocular infiltration in the disease course. The first case was a 67-year-old woman who developed bilateral vitreous opacity about half a year after the onset of acute type of ATLL that had been unresponsive to chemotherapy. She underwent vitrectomy combined with cataract surgery in both eyes. She had bilateral optic disc atrophy and localized retinal white infiltrates in both eyes. Cytological examination of vitreous aspirates demonstrated medium-sized cells with aberrant flower-like convoluted nuclei, positive for CD3, and thus indicative of T-cells. The second case was a 38-year-old man who was diagnosed acute type of ATLL at the presentation of acute kidney injury. About half a year after initial chemotherapy and allogeneic hematopoietic stem cell transplantation, he developed aqueous hypopyon in the right eye, concurrent with cutaneous and central nervous system relapse. Aqueous tap disclosed class V abnormal cells. The aqueous “pseudohypopyon” resolved in response to another round of chemotherapy with mogamulizumab. In review of 18 patients, intraocular infiltration with ATLL was diagnosed by vitrectomy in 9, aqueous tap in 3, chorioretinal biopsy in 3, and autopsy in 3. The intraocular infiltration developed concurrently with systemic diagnosis of ATLL in 5 patients, but developed later after chemotherapy in 13. In conclusion, intraocular infiltration with ATLL appears rare, and pathological diagnosis by vitrectomy and aqueous tap would help determine therapeutic plan in relapse after chemotherapy.

Response: Estimating frequency of cancer stem cells in a mouse model of adult T-cell leukemia/lymphoma

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2118-2118
Author(s):  
Jumpei Yamazaki ◽  
Takuo Mizukami ◽  
William W. Hall ◽  
Isao Hamaguchi
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cancer Stem Cells ◽  
Mouse Model ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

Unrelated Bone Marrow Transplantation for Adult T Cell Leukemia/Lymphoma: A Study from the Japan Marrow Donor Program.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2059-2059
Author(s):  
Koji Kato ◽  
Yoshinobu Kanda ◽  
Tetsuya Eto ◽  
Tsuyoshi Muta ◽  
Hisashi Gondo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Disease Status ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Unrelated Bone Marrow Transplantation ◽  
Adult T Cell Leukemia ◽  
Related Donor

Abstract Adult T cell leukemia/lymphoma(ATLL) is known to be a very poor prognosis, and intensified chemotherapy has not yet improved this prognosis. Some successful cases of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched siblings have been reported and allo-HSCT has been suggested as improving the prognosis of ATLL. However, HLA-matched related donor is seldom available and about two-thirds of siblings of patients with ATLL are HTLV-1 carriers. Although most of ATLL patients require an unrelated donor to benefit from allo-HSCT, there is little information about the outcome of unrelated bone marrow transplantation(UBMT) for ATLL. To elucidate the feasibility and efficacy of UBMT from HTLV-1 seronegative donor, we retrospectively analyzed the data of 33 patients who were ATLL and underwent UBMT through the Japan Marrow Donor Program. Median age of patients at transplantation was 51 years(range,24–59). The conditioning regimens of 27 patients had myeloablative intensity and 6 had reduced intensity. At transplantation, 12 patients were in complete remission, 3 were partial remission and 14 were no remission. A total of 14 patients died after allo-HSCT, and 9 of those 14 patients were lost within 100 days after HSCT due to treatment related adverse events. The overall survival(OS), progression-free survival(PFS), cumulative incidences of disease progression, and nonprogression mortality at 2 years after UBMT were 49.7%, 42.6%, 24.5%, and 32.9%, respectively. Multivariate analysis demonstrated that recipient age(P=.044) and disease status at transplantation(P=.059) were independent prognostic factors for OS and PFS. These results suggest that UBMT could be considered as a treatment option for ATLL patients without an HLA-matched related donor. Further study is required to determine the indication of nonmyeloablative conditioning based on patient’s age or disease status, because myeloablative conditioning had high incidence of treatment related mortality.

Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID Mice Engrafted With Adult T-Cell Leukemia Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4747-4751 ◽  
Author(s):  
Akifumi Takaori-Kondo ◽  
Kazunori Imada ◽  
Itsuo Yamamoto ◽  
Akane Kunitomi ◽  
Yasuharu Numata ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
T Cell ◽  
Scid Mice ◽  
T Cell Leukemia ◽  
Related Protein ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Adult T-Cell Leukemia/Lymphoma

2014 ◽  
Vol 138 (2) ◽  
pp. 282-286 ◽  
Author(s):  
Sohail Qayyum ◽  
John K. Choi
Keyword(s):  
T Cell ◽  
Adult Population ◽  
The United States ◽  
Cd4 T Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cell Neoplasm ◽  
The Caribbean

Adult T-cell leukemia/lymphoma is a rare mature CD4+ T-cell neoplasm caused by the retrovirus human T-lymphotrophic virus type 1. At present there are approximately 20 million people infected globally with this virus, and most of these individuals belong to the endemic areas in southern Japan, Africa, the Caribbean basin, and Latin America. In the United States, it is usually seen in immigrants from these endemic regions. Adult T-cell leukemia/lymphoma predominantly affects the adult population and is rare in children. Adult T-cell leukemia/lymphoma has 4 subtypes: acute, lymphomatous, chronic, and smoldering. Clinically, the first 2 variants are classified as aggressive, and the latter two are classified as indolent. Given the rare occurrence and diagnostic challenges associated with adult T-cell leukemia/lymphoma, this review will highlight its salient features to aid in recognition of this entity and perform a comprehensive diagnostic workup.

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