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Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice.

ABSTRACT: The treatment of chronic lymphocytic leukemia (CLL) has been improved dramatically by inhibitors targeting B-cell receptor (BCR)-associated kinases. The tyrosine kinase Lyn is a key modulator of BCR signaling and shows increased expression and activity in CLL. To evaluate the functional relevance of Lyn for CLL, we generated a conditional knockin mouse model harboring a gain-of-function mutation of the Lyn gene (LynY508F), which was specifically expressed in the B-cell lineage (Lynup-B). Kinase activity profiling revealed an enhanced responsiveness to BCR stimulation in Lynup-B B cells. When crossing Lynup-B mice with Eµ-TCL1 mice (TCL1tg/wt), a transgenic mouse model for CLL, the resulting TCL1tg/wt Lynup-B mice showed no significant change of hepatomegaly, splenomegaly, bone marrow infiltration, or overall survival when compared with TCL1tg/wt mice. Our data also suggested that TCL1 expression has partially masked the effect of the Lynup-B mutation, because the BCR response was only slightly increased in TCL1tg/wt Lynup-B compared with TCL1tg/wt. In contrast, TCL1tg/wt Lynup-B were protected at various degrees against spontaneous apoptosis in vitro and upon treatment with kinase inhibitors targeting the BCR. Collectively, and consistent with our previous data in a Lyn-deficient CLL model, these data lend further suggest that an increased activation of Lyn kinase in B cells does not appear to be a major driver of leukemia progression and the level of increased BCR responsiveness induced by Lynup-B is insufficient to induce clear changes to CLL pathogenesis in vivo.

SUBMITTER: Kohlhas V

PROVIDER: S-EPMC7756995 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice.

Kohlhas Viktoria V Hallek Michael M Nguyen Phuong-Hien PH

Blood advances 20201201 24

The treatment of chronic lymphocytic leukemia (CLL) has been improved dramatically by inhibitors targeting B-cell receptor (BCR)-associated kinases. The tyrosine kinase Lyn is a key modulator of BCR signaling and shows increased expression and activity in CLL. To evaluate the functional relevance of Lyn for CLL, we generated a conditional knockin mouse model harboring a gain-of-function mutation of the Lyn gene (LynY508F), which was specifically expressed in the B-cell lineage (Lynup-B). Kinase ...[more]

PMID: 33351104

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Project description:Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal of T-cell dysfunction in CLL may be beneficial to reduce tumor burden. Previous studies have also highlighted roles for histone deacetylase 6 (HDAC6) in regulation of immune cell phenotype and function. Here, we report for the first time that HDAC6 inhibition exerts beneficial immunomodulatory effects on CLL B cells and alleviates CLL-induced immunosuppression of CLL T cells. In the Eμ-TCL1 adoptive transfer murine model, genetic silencing or inhibition of HDAC6 reduced surface expression of programmed death-ligand 1 (PD-L1) on CLL B cells and lowered interleukin-10 (IL-10) levels. This occurred concurrently with a bolstered T-cell phenotype, demonstrated by alteration of coinhibitory molecules and activation status. Analysis of mice with similar tumor burden indicated that the majority of T-cell changes elicited by silencing or inhibition of HDAC6 in vivo are likely secondary to decrease of tumor burden and immunomodulation of CLL B cells. The data reported here suggest that CLL B cell phenotype may be altered by HDAC6-mediated hyperacetylation of the chaperone heat shock protein 90 (HSP90) and subsequent inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Based on the beneficial immunomodulatory activity of HDAC6 inhibition, we rationalized that HDAC6 inhibitors could enhance immune checkpoint blockade in CLL. Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the Eμ-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8+ T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients.

Dataset Information

Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice.

Publications

Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice.

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