Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia

Abstract

NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EμSRα enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis. We also observed the development of skin keratoacanthoma lesions, probably because of aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene on doxycycline treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease. Importantly, treatment with the specific ALK inhibitor (PF-2341066) also reversed the pathologic states, showing the value of these mouse models for the validation of ALK tyrosine kinase inhibitors. Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases. Our models offer a new tool to investigate in vivo the molecular mechanisms associated with ALK-induced lymphoproliferative disorders.

Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas

“…14,29 In this study we have demonstrated that miR-16 is downregulated upon ALK expression both in vitro and in vivo using our onco-ALK conditional cellular and mouse models for ALK tumorigenesis. 25,26 Importantly, a weaker expression of miR-16 was also observed in ALK þ ALCL patients when compared with ALKÀ ALCL patients.…”

“…In this study, we have used onco-ALK (NPM-ALK and TPM3-ALK) cellular and mouse models conditional for ALK expression 25,26 to report for the first time, an increase in VEGF secretion both in vitro and in vivo. The increase in VEGF secretion in these models was not seen in normal cells, that is, following doxycycline-induced onco-ALK inactivation.…”

“…Generation of conditional transgenic mice and MEF Tet-OFF cells (Clontech, Saint Quentin Yvelines, France) for expression of NPM-ALK or TPM3-ALK oncogenes was described by Giuriato et al 25,26 The tetracycline regulatory system was used to control the transgene transcription. The addition of doxycycline (an analog of tetracycline) allowed silencing of onco-ALK expression (OFF condition, ALK-), whereas doxycycline removal permitted onco-ALK expression (ON condition, ALK þ ).…”

“…Here, we used onco-ALK (NPM-ALK and TPM3-ALK) mouse conditional MEF cell line (ALK þ fibroblasts), 25 as well as transgenic models (ALK þ B-lymphoma), 26 to both determine whether ALK oncogenes regulate VEGF levels and tumor angiogenesis and investigate the mechanisms involved.…”

ALK+ALCLs induce cutaneous, HMGB-1–dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation

“…We recently developed a conditional mouse model for NPM-ALK-induced lymphomagenesis, which develops lymphoma that is associated with hyperplasia of the epidermis (acanthosis lesions). 22 In 30% of these mice, a lymphomatous infiltration is observed in the dermis below the cutaneous lesions. In this model, we also observed an up-regulation of HMGB-1 mRNA in the lymph nodes and an increase in the serum of CXCL1 (also termed KC), the murine IL-8 functional homolog.…”