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New Therapeutic Strategies for Adult T Cell Leukemia/Lymphoma (ATLL)

Leukemia, lymphoma, and myeloma are the most prevalent types of blood/bone marrow cancers in the US today. Leukemia accounted for 34% (60,000 individuals) of all blood cancers in 2020 and it is estimated that over 61,000 individuals will be diagnosed with leukemia in 2021 (https://cancerstatisticscenter.cancer.org/#!/cancer-site/Leukemia ).

Bone marrow is the primary site of hematopoiesis in the body, where hematopoietic stem cells differentiate into lymphoid and myeloid lineages, which form all the mature cell types necessary to maintain peripheral blood homeostasis. Leukemia begins in the developing white blood cells in the bone marrow where mutations cause abnormal and uncontrollable growth. The widespread prevalence of blood cancers has driven active research into improving our mechanistic knowledge of disease onset and progression to aid efforts in developing novel therapeutics that can effectively treat the disease.

Lifeline® offers a wide range of high-quality peripheral blood mononuclear cells and subtypes including:

New Research Using Lifeline’s PBMCs

In our latest publication review, Ishikawa and Colleagues utilized Lifeline’s peripheral blood mononuclear cells (PBMCs) to investigate the role of the importin protein, IPOβ1, in pathogenesis of adult T cell leukemia/lymphoma (ATLL), which is caused by latent infection with human T cell leukemia virus type 1 (HTLV-1), in hopes of developing novel therapeutic strategies. Allogenic hematopoietic stem cell transplantation is the only curative therapy, but its efficacy is limited because ATLL develops primarily in the elderly. Therefore, more effective and less toxic therapeutic options are highly desirable.

Studies have shown that HTLV-1-infected T cells and ATLL cells demonstrate constitutive NF-κB and AP-1 activation where IPOβ1 is a major nuclear transport factor for both transcription factors to activate target genes in the nucleus, but its role in ATLL is not well defined. The activation of NF-κB and AP-1 initiates the expression of various target genes that contribute to cancer progression by enhancing cell cycle progression (proliferation) and regulating apoptosis (mediating the evasion of apoptosis). Moreover, IPOβ1 upregulation is observed in various cancers, including cervical and lung cancer correlates with poor patient prognosis and thus it could be a promising novel therapeutic target.

In this study, the researchers quantified the expression of IPOβ1 in vitro in HTLV-1 infected T cell lines compared to PBMCs from healthy donors. IPOβ1 expression, analyzed by western blotting and RT-PCR, was found to be upregulated in HTLV-1 infected cells compared to normal PBMCs, and co-culture of HTLV-1 cells with normal PBMCs increased IPOβ1 levels suggesting a direct link between HTLV-1 infection and IPOβ1 expression.

The cellular function of IPOβ1 was determined using siRNA knockdown or the IPOβ1 inhibitor importazole and the IPOα/ β1 inhibitor ivermectin. HTLV-1- infected T cell growth was suppressed in IPOβ1 knockdown assays and cellular viability was reduced with IPOβ1 inhibitors (assessed by water-soluble tetrazolium (WST)-8 assay). This reduction was found to be from activation of caspase apoptosis pathways and reduction in levels of anti-apoptotic proteins survivin, c-IAP1/2, and XIAP. The IPOβ1 inhibitors also acted on NF-κB and AP-1 target proteins cyclin D1/D2/E, CDK2/4/6, and c-Myc, which are necessary for cell cycle transition from G1 to S phase. The IPOβ1 inhibitors were effectively able to mitigate the cell cycle progression and anti-apoptotic events caused by constitutively active NF-κB and AP-1 in HTLV-1 infected T cells, which led the researchers to perform confirmatory in vivo studies.

Xenograft tumors in a mouse model (HUT-102) were used to evaluate the growth of ATLL cells in vivo. Ivermectin effectively suppressed tumor growth and signs of apoptosis such as chromatin condensation and cell shrinkage were observed. Overall, the results indicate that the IPOβ1 inhibitor exerts an anti-tumor effect in an in vivo ATLL model with minimal side effects.

The results from this publication demonstrate the inhibition of IPOβ1 could be a way to specifically target and control the overactive transcription factors NF-κB and AP-1 that play a primary role in cell cycle progression and survival in ATLL cells. Ivermectin is currently a licensed anti-strongyloidiasis medication, and although no prior clinical studies have directly evaluated its use as an anti-ATLL agent, the in vivo results from the study presented here suggests that it could be an effective IPOβ1 inhibitor to treat ATLL and warrants further investigation.

Have you used Lifeline’s PBMCs in your research? If so, we would love to hear from you to showcase your work here on the blog.

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