Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia

Abstract

Interestingly, the addition of an anti-IL-2R-␣ monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/ IL-9, and the downstream Janus kinase/ signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. IntroductionAdult T-cell leukemia (ATL) that is caused by human T-cell lymphotropic virus I (HTLV-1) is an aggressive malignancy of CD4-and CD25-expressing leukemia, and lymphoma cells. ATL is a heterogeneous disease that can be divided broadly into 4 stages: smoldering, chronic, lymphoma, and acute-type ATL. The common clinical manifestations of ATL are skin lesions, hypercalcemia, immunologic anergy to antigen stimulation, and cells with "flowerlike" nuclei in the circulation. Smoldering/chronic ATL patients have normal or mildly increased white blood cell counts with a variable number of leukemic cells in the circulation and are generally associated with a better prognosis. Patients with acutetype ATL have organ dysfunction associated with circulating leukemic cells and are generally associated with a poor prognosis. The mechanisms underlying the progression from smoldering/chronic stage to the acute stage are unknown; however, the accumulation of molecular mutations is thought to play a role in this progression.Although the pathogenesis of ATL is unknown, the virally encoded regulatory protein, HTLV-1 Tax, seems to play a central role in the initial leukemogenesis of ATL. Hasegawa et al demonstrated that overexpression of Tax in immature thymocytes induced leukemia/lymphoma in mice with clinical, pathologic, and immunologic features characteristic of ATL after a long latency. 1 Subsequently, Ohsugi et al 2 showed that Tax is able to promote oncogenesis not only with immature T cells, but also with mature T cells. Both experiments highlighted the importance of Tax in the initial development of ATL.Beyond the in vivo mouse models, numerous in vitro studies have demonstrated the essential role of Tax in ATL initiation and shed light on the mechanism of Tax-mediated cellular transformation. 3 Tax deregulates the expression of genes involved in cellular proliferation, cell-cycle control, and apoptosis through physical interaction with cellular elements, including transcription factors such as nuc...

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

“…These autocrine/paracrine loops are associated with spontaneous ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients. Targeted antibodies to IL-2, IL-9, and IL-15 or their receptors significantly inhibit ex vivo proliferation of PBMCs from smoldering/chronic ATL patients (10,11). These three cytokines share the common γc cytokine receptor subunit that triggers JAK/STAT signaling, and we noted antiproliferative effects for selected JAK inhibitors in PBMCs from smoldering/chronic ATL patients (11).…”

“…Previously we demonstrated that HTLV-1-encoded Tax transactivates two autocrine (IL-2/IL-2Rα, IL-15/IL-15Rα) loops and one paracrine loop (IL-9) that signal through the JAK/STAT pathway and that proliferation of ex vivo PBMCs from smoldering/chronic ATL patients were sensitive to JAK inhibition (7)(8)(9)(10)(11). To expand the scope of these results, we acquired numerous human ATL cell lines including IL-2-dependent and IL-2-independent lines.…”

“…It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that involves IL-9 expression by ATL cells in the early stages of the disease (7)(8)(9)(10). These autocrine/paracrine loops are associated with spontaneous ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients.…”

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

“…Indeed, most ATL cells do not express Tax and tend to become independent of IL-2 (9), in particular in acute ATL. Nevertheless, IL-2 is often required for ATL cell proliferation and survival, suggesting the importance of IL-2 in tumor growth in some patients, such as those suffering from chronic ATL, regardless of Tax protein expression (10,11).…”

Establishment of cell lines from adult T-cell leukemia cells dependent on negatively charged polymers

“…Generally, ATLL cells die ex vivo due to apoptosis, which is inhibited by the addition of interleukin (IL)-2 7 , although IL-2 does not support acute-type ATLL cell growth 8 . With regard to the microenvironment of different organs where ATLL was involved, interaction with the surrounding cells was suspected.…”