four to six weeks [22]. Although these models do not precisely mimic human ALCL in humans, they provide versatile tools to examine NPM1‐ALK signaling pathways in vivo.
Transgenic Models
Chiarle et al. reported the first transgenic mouse in which NPM1‐ALK expression was driven by the Cd4 promoter developed thymic lymphomas and plasmacytomas [23]. They further demonstrated the pathogenic roles of STAT3 in ALCL with NPM1‐ALK expression using the mice [24]. Subsequently, Turner et al. generated mice transgenic for a human NPM1‐ALK fusion gene regulated by the hematopoietic cell‐specific Vav promoter [25]. These mice exhibited development of B‐cell lymphomas and plasmacytomas. Similarly, transgenic mice expressing the NPM1‐ALK transgene regulated by the T cell‐specific Cd2 promoter also developed B‐lymphoid malignancies with variable histological features [26].
CRISPR‐Based Models
In 2019, Rajan et al. used gene editing to establish a mouse model of ALCL, ALK+ after transplantation of hematopoietic stem cells with Npm1‐Alk generated by a CRISPR‐Cas9 method [27]. The lymphoma cells had a large‐cell morphology with CD30 expression accompanied by oligoclonal TCR rearrangements. These features were compatible with those of ALK‐positive ALCL. Therefore, this method may replace traditional approaches to modeling of ALCL in mice.
PDX Models of Anaplastic Large‐Cell Lymphomas
Pfeifer et al. reported a PDX model in which cells from a patient with systemic CD30+ ALCL resistant to chemotherapy were transplanted into severe immunodeficient (SCID) mice [28]. They showed that human ALCL tumor cells xenografted and then serially passaged into SCID mice maintained the original characteristics of the patient’s tumor. This model was also used to demonstrate anti‐tumor effects of the agonistic anti‐human CD30 antibody HeFi‐1 on development of CD30+ ALCL tumors in mice.
Human T‐cell Lymphotropic Virus Type 1 Adult T‐cell Leukemia/Lymphoma
ATLL is caused by persistent infection of the human T‐cell lymphotropic virus type 1 (HTLV1). Clinical presentation of ATLL varies from relatively indolent forms to aggressive forms. ATLL develops only a small part of HTLV1 carriers after an incubation period of about 60 years from HTLV1 infection [1]. Additional genetic and epigenetic abnormalities are thought to be required for the onset of ATLL. In addition to gag, pol and env genes, the HTLV1 genome encodes accessory proteins including Tax, a transcriptional activator and HTLV1 basic leucine zipper factor (HBZ), a nuclear protein, both of which play essential roles in cellular proliferation, survival, and genetic stability of ATLL cells [29].
Mice Expressing HTLV‐1 Viral Proteins
Several lines of transgenic mice expressing Tax under the control of viral promoters HTLV1 long terminal repeat have been developed. These mice develop mesenchymal tumors [30], arthritis [31], and osteoporosis [32]. Mesenchymal tumors were observed in the nose, ear, foot, and tail and were characterized by a spindle‐cell component and granulocyte infiltration. However, these models do not mimic human ATLL. Other investigators generated Tax transgenic mice using promoters activated in T cells [33, 34]. Among these, transgenic mice expressing Tax from the Cd3‐epsilon promoter developed a variety of tumors dependent on the lines, including mesenchymal tumors, and salivary and mammary adenomas [33]. Transgenic mice expressing Tax in thymocytes under control of the Lck proximal promoter developed thymic T‐cell lymphomas [34]. Moreover, the other transgenic mice expressing Tax using the GrzmB promoter developed large granular lymphocytic leukemia, lymphadenopathy, extranodal disease and hypercalcemia, resembling human ATLL [35, 36].
Transgenic mice expressing HBZ have also been developed [37, 38]. Mice expressing HBZ driven by the Cd4 promoter showed inflammatory lesions of lung and skin, accompanied by increase of effector/memory and regulatory CD4+ T cells [37]. Approximately 40% of these mice also develop T‐cell lymphomas after a long latency, reminiscent of human ATL. HBZ transgenic mice constructed using the GrzmB promoter were also reported [38] and exhibited lymphoproliferative disease, osteoporosis, splenomegaly, and hypercalcemia, similar to lymphoma‐type of ATLL. HBZ/Tax double transgenic mice in which both genes were controlled by the Cd4 promoter showed phenotypes similar to those of HBZ single transgenic mice [39]. Despite this progress, to date a model fully replicating human ATLL disease has not yet been established likely due to the complexity of the human ATLL disease.
PDX Models of Adult T‐cell Leukemia/Lymphoma
Xenograft mouse models transplanted with ATLL patient‐derived cells have been examined [40]. In these models, immunodeficient SCID and NOD/SCID recipient mice displayed multiple features of human ATLL disease, namely, aberrant lymphocyte infiltration in liver, spleen, lung, peritoneum, and other organs. These models have helped define mechanisms underlying HTLV1 infection, clonal proliferation and the immune response against HTLV1 and have contributed to development of targeted therapies. For example, treatments using the antibody against C─C chemokine receptor type 4 and an inhibitor of histone deacetylase have been tested in these models.
Cutaneous T‐cell Lymphoma
CTCL contains a broad spectrum of diseases: Mycosis fungoides and Sézary syndrome account for more than 60% of CTCL. The tumor cells of Mycosis fungoides and Sézary syndrome represent CD4+ helper T cells. Several CTCL models have been established to define mechanisms underlying CTCL and identify therapeutic targets. Patients with CTCL show high IL‐15 protein levels in the skin. Hypermethylation within the IL‐15 promoter suppresses binding of the ZEB1 transcriptional repressor to the locus, leading to increase of IL‐15 transcription in CD4+ T cells [41]. Fehniger et al. reported a transgenic mouse model using the MHC class I promoter to drive IL‐15 expression [42]. IL‐15 transgenic mice developed fatal leukemia with involvement of multiple organs including skin around 12–30 weeks and have served as a preclinical CTCL model and were useful in the discovery that interruption of IL‐15 signaling via an HDAC inhibitor is a promising treatment strategy for CTCL [41, 42].
JAK3‐activating mutations are recurrently observed in CTCL [43]. Human JAK3 shows four mutation hotspots: M511I, R657Q, A572V, and 573V. Cornejo et al. reported the retroviral transduction of active JAK3A572V mutant cDNA into 5‐fluorouracil‐treated murine bone marrow cells followed by transplantation into lethally irradiated mice [44]. The recipient mice developed CD8+ lymphoproliferative diseases with skin involvement, mimicking a leukemic form of CTCL [44]. Rivera‐Munoz et al. generated a JAK3A572V knock‐in mouse model expressing the JAK3A572V mutant from the endogenous Jak3 locus also developed a leukemic form of CTCL [45]. Phosphorylation of downstream targets of JAK3 was dose dependent: phospho‐Stat3 and Stat5 were observed even in thymocytes from heterozygous JAK3A572V mutant mice, while phospho‐Akt and Erk1/2 were seen only in those of homozygous. Treatment with tofacitinib, a pan‐JAK inhibitor reduced growth of JAK3A572V‐positive CD4+ and CD8+ malignant cells. This result suggests that inhibition of constitutively activated JAK3 may improve treatment outcomes of CTCLs.
Enteropathy‐associated T‐cell Lymphoma
EATL is a rare but fatal PTCL arising from the intestinal tract. Genomic alterations in SETD2 gene resulting in SETD2 loss of function, and/or loss of the corresponding 3p.21 locus are found in 31–86% of EATL [46, 47]. SETD2 encodes a non‐redundant H3K36‐specific tri‐methyltransferase
