Читать книгу The Peripheral T-Cell Lymphomas - Группа авторов - Страница 71

Peripheral T‐cell lymphomas (PTCL) are a heterogeneous group of blood cancers with varying pathological and clinical features. Standard chemotherapy approaches for most PTCL are not yet well established, with the exception of anaplastic lymphoma kinase positive (ALK+) anaplastic large‐cell lymphoma (ALCL). Thus, better understanding of the molecular pathogenesis of these intractable diseases is warranted to develop effective therapies. In that effort, analysis of samples collected from patients with PTCL has been the gold standard for analysis of gene and protein expression, as well gene mutational profiles. However, it remains challenging to discover fundamental mechanisms that could be targeted based on analysis of samples with such heterogeneous backgrounds. Also, both the initiation and dynamic course of these diseases are difficult to pinpoint due to limitations on sample collection by their rarity. Nonetheless, recent analysis of patient samples has identified some mutational profiles and expression signatures for various types of PTCL that can be modeled in mice, which is an essential step in developing novel treatments.

In this chapter we describe several mouse lines established for angioimmunoblastic T‐cell lymphoma (AITL), ALCL, adult T‐cell leukemia/lymphoma (ATLL), cutaneous T‐cell lymphoma (CTCL) and enteropathy‐associated T‐cell lymphoma (EATL) (Summarized in Table 4.1). Most of the mouse lines are established by transgenic or knock‐in strategies commonly used to express oncogenes identified in patient samples. One advantage of transgenic models is that the transgene can be engineered to be expressed tissue‐specifically or responsive to a particular drug. Knock‐in models are superior to transgenic models in that oncogenic genes are expressed at physiological levels. Clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9, a powerful genome‐editing tool has begun to be incorporated in this research area. Moreover, patient‐derived xenograft (PDX models have been established by inoculating patient samples into immunodeficient mice. Ultimately, a combination of all these approaches will be necessary to understand mechanisms driving initiation and progression of PTCL.

Table 4.1 Mouse models of peripheral T‐cell lymphomas (PTCL)

Types of PTCL	Models	Methods	Phenotypes of mice	Others (downstream signaling, etc.)	Reference
AITL	Roquinsan	Heterozygous for Roquinsan : a missense (M199R) sanroque mutation in the Roquin gene	Increase of TFH cells AITL‐like disease around 4 to 15 months	No ROQUIN gene alterations in human AITL	Ellyard4
Tet2 gene trap	A gene‐trap vector inserted into the Tet2 second intron	Development of T‐cell lymphomas with TFH‐like phenotype around 67 weeks	Hypermethylation of silencer region of Bcl6 gene	Muto10
G17V RHOA	G17V RHOA cKI mice crossed with CD4Cre‐ERT2	Increase of TFH cells		Cortes14
G17V RHOA transgenic mice under the Cd4 promoter	Increase of TFH cells Autoimmunity		Ng15
G17V RHOA transgenic mice under the CD2 promoter	No phenotype		Nguyen16
G17V RHOA‐Tet2 null	Retroviral transduction of G17V RHOA mutant cDNA into Tet2‐null T cells	Increase of TFH cells CD4+ proliferation	Inactivation of FoxO1	Zang13
G17V RHOA cKI mice crossed with CD4CreERT2 and Tet2cKO with SRBC immunization	AITL‐like disease around 25 weeks	ICOSL‐ICOS signaling Activation of PI3K‐mTOR signaling	Cortes14
G17V RHOA transgenic mice crossed with Tet2cKO x Vav‐Cre, and OT‐II mice with NP‐40‐Ovalbumin immunization	AITL‐like disease around 38 weeks	Activation of PI3K‐mTOR signaling	Ng15
G17V RHOA transgenic mice crossed with Tet2cKO x Mx1‐Cre mice	AITL‐like disease around 48 weeks	Activation of T‐cell receptor signaling	Nguyen16
PDX	Inoculation of cells from lymph nodes of AITL patients into NOD/Shi‐scid, IL2Rgammanull (NOG) mice	AITL‐like disease	Detection of human immunoglobulin G/A/M in the sera	Sato18
ALCL	NPM1‐ALK	Retroviral transduction of NPM1‐ALK cDNA into 5‐ fluorouracil‐treated murine BM	B‐lineage large cell lymphomas around 4‐6 months		Kuefer20
Retroviral transduction of NPM1‐ALK cDNA with low versus high multiplicity of infection (MOI)	Plasmacytomas around 12‐16 weeks with lower MOI, Histiocytic malignancies around 3‐4 weeks with higher MOI		Miething21
Retroviral transduction of Lox‐STOP‐Lox‐NPM1‐ALK encoding vector in BM expressing Cre under the LyzM-promotor or GrzmB‐promotor	Histiocytic malignancies around 4‐6 weeks for LyzM, Mixed phenotype of T‐cell lymphoma/ histiocytic malignancy around 4‐6 weeks for GrzmB		Miething22
NPM1‐ALK transgenic mice under the Cd4 promoter	Thymic lymphomas and plasmacytomas around 18 weeks	Activation of Stat3 signaling	Chiarle23,24
NPM1‐ALK transgenic mice under the Vav1 promoter	Diffuse large B‐cell lymphomas with high copy number Plasmacytomas with low copy number		Turner25
NPM1‐ALK transgenic mice under the Cd2 promoter	B‐cell lymphomas with variable histological features		Turner26
CRISPR‐based models to make Npm1‐Alk in HSC	ALCL, ALK+‐like disease		Rajan27
PDX	Cells from a patient with systemic CD30+ ALCL resistant to chemotherapy were inoculated into SCID mice	ALCL, ALK+‐like disease		Pfeifer28
ATL CTCL	TAX HBZ	Tax transgenic mice under the control of viral promoters, HTLV‐1 LTR	Mesenchymal tumors, arthritis, and osteoporosis		Nerenberg30, Habu31, and Ruddle32
Tax transgenic mice under the Cd3‐epsilon promoter	Mesenchymal tumors, and salivary and mammary adenomas		Hall33
Tax transgenic mice under the Lck proximal promoter	Thymic T‐cell lymphomas		Hasegawa34
Tax transgenic mice under the GrzmB promoter	LGL and hypercalcemia		Grossman35 Gao36
	HBZ transgenic mice under the Cd4 promoter	Increase of effector/memory and regulatory CD4+ T cells Inflammation of lung and skin		Satou37
	ATL‐like disease after long latencies
HBZ transgenic mice under the GrzmB promoter	ATL‐like disease with osteoporosis and hypercalcemia around 18 months		Esser38
PDX	Inoculation of cells from ATL patients to immunodeficient (SCID and NOD/SCID) mice	ATL‐like disease		Kawano40
	IL‐15	Transgenic mice expressing a modified IL‐15 cDNA under the MHC class I promoter	A leukemic form of CTCL around 12‐30 weeks	Upregulation of HDAC	Fehniger41
JAK3A572V mutant	Retroviral transduction of JAK3A572V into 5‐fluorouracil-treated murine BM JAK3A572V knock‐in mouse model	A leukemic form of CTCL A leukemic form of CTCL		Cornejo44 Rivera‐Munoz45
EATL	Setd2	Setd2 conditional knockout mice crossed with Lck‐Cre transgenic mice	Increase of the intraepithelial γδ‐positive T cells		Moffitt47

PTCL, peripheral T‐cell lymphoma; AITL, angioimmunoblastic T‐cell lymphoma; ALCL, anaplastic large cell lymphoma; ATL, adult T‐cell leukemia/lymphoma; CTCL, cutaneous T‐cell lymphoma; EATL, enter-opathy‐associated T‐cell Lymphoma; TFH, T follicular helper; cKI, conditional knock in; cKO, conditional knockout; SRBC, sheep red blood cells; PDX, patient‐derived xenograft; BM, bone marrow; LyzM, Lysozyme M; GrzmB, granzyme B; HSC, hematopoietic stem cells; SCID, severe immunodeficient mice; LTR, long terminal repeat; LGL, large granular lymphocytic leukemia