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TheE mu-TCL1transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individualE mu-TCL1transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion ofTp53besides theTCL1transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of theE mu-TCL1transgenic cohorts in future studies.

CD74 is a surface protein expressed on immune cells, which acts as receptor for the chemokine macrophage migration inhibitory factor (MIF). Signalingviathe MIF/CD74-axis has been reported to be important for the pathogenesis of chronic lymphocytic leukemia (CLL). We wanted to clarify the role of CD74 in MIF-induced signaling/leukemic development. In E mu-TCL1 transgenic mice, occurrence of the leukemic phenotype was associated with increased surface CD74 expression. E mu-TCL1(+/+)Cd74(-/-)mice showed similar kinetics and clinical features of CLL development as E mu-TCL1(+/+)mice. MIF stimulation of leukemic splenocytes led to AKT activation in a CD74-dependent manner. AKT activation was reduced in Cd74-deficient splenocytes in the presence of the oncogenic TCL1-transgene. Tumor cell apoptosis/proliferation were unaffected in E mu-TCL1(+/+)Cd74(-/-)mice. Our data suggest that the need for active CD74 signaling is overcome in the leukemic context of TCL1-driven CLL, and that CD74 may have a dispensable role for CLL pathogenesis in this model.

TheE mu-TCL1transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individualE mu-TCL1transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion ofTp53besides theTCL1transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of theE mu-TCL1transgenic cohorts in future studies.

CD74 is a surface protein expressed on immune cells, which acts as receptor for the chemokine macrophage migration inhibitory factor (MIF). Signalingviathe MIF/CD74-axis has been reported to be important for the pathogenesis of chronic lymphocytic leukemia (CLL). We wanted to clarify the role of CD74 in MIF-induced signaling/leukemic development. In E mu-TCL1 transgenic mice, occurrence of the leukemic phenotype was associated with increased surface CD74 expression. E mu-TCL1(+/+)Cd74(-/-)mice showed similar kinetics and clinical features of CLL development as E mu-TCL1(+/+)mice. MIF stimulation of leukemic splenocytes led to AKT activation in a CD74-dependent manner. AKT activation was reduced in Cd74-deficient splenocytes in the presence of the oncogenic TCL1-transgene. Tumor cell apoptosis/proliferation were unaffected in E mu-TCL1(+/+)Cd74(-/-)mice. Our data suggest that the need for active CD74 signaling is overcome in the leukemic context of TCL1-driven CLL, and that CD74 may have a dispensable role for CLL pathogenesis in this model.

Survival of chronic lymphocytic leukemia (CLL) cells strictly depends on the support of an appropriate tumor microenvironment. Here, we demonstrate that LYN kinase is essential for CLL progression. Lyn deficiency results in a significantly reduced CLL burden in vivo. Loss of Lyn within leukemic cells reduces B cell receptor (BCR) signaling including BTK phosphorylation, but surprisingly does not affect leukemic cell expansion. Instead, syngeneic CLL transplantation of CLL cells into Lyn- or Btk-deficient recipients results in a strongly delayed leukemic progression and prolonged survival. Moreover, Lyn deficiency in macrophages hinders nursing functions for CLL cells, which is mediated by direct contact rather than secretion of soluble factors. Taken together, LYN and BTK seem essential for the formation of a microenvironment supporting leukemic growth.

Survival of chronic lymphocytic leukemia (CLL) cells strictly depends on the support of an appropriate tumor microenvironment. Here, we demonstrate that LYN kinase is essential for CLL progression. Lyn deficiency results in a significantly reduced CLL burden in vivo. Loss of Lyn within leukemic cells reduces B cell receptor (BCR) signaling including BTK phosphorylation, but surprisingly does not affect leukemic cell expansion. Instead, syngeneic CLL transplantation of CLL cells into Lyn- or Btk-deficient recipients results in a strongly delayed leukemic progression and prolonged survival. Moreover, Lyn deficiency in macrophages hinders nursing functions for CLL cells, which is mediated by direct contact rather than secretion of soluble factors. Taken together, LYN and BTK seem essential for the formation of a microenvironment supporting leukemic growth.

To assess the effects of chemoimmunotherapy on post-chemotherapy cognitive impairments (PCCI) in patients with B-cell non-Hodgkin lymphoma (NHL), we used objective and subjective measures of cognitive functions in combination with serum parameters and neuroelectric recordings. Self-perceived status of cognition, fatigue and emotional functioning were reduced in patients (n = 30) compared to healthy controls (n = 10). Cognitive performance was impaired in patients with NHL compared to controls and a norm sample (n = 1179). PCCI was more severe in patients treated with rituximab and bendamustine (BR) than in patients who received R in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) polychemotherapy (R-CHOP). Individual alpha peak frequency and serum brain-derived neurotrophic factor (BDNF) levels in patients with NHL correlated with accuracy in the objective cognition test. Higher serum interleukin-6 (IL-6) concentrations were associated with higher fatigue levels. Patients with NHL and especially those who were treated with BR were affected by PCCI. BDNF and IL-6 might be involved in the pathogenesis of PCCI and fatigue.

To assess the effects of chemoimmunotherapy on post-chemotherapy cognitive impairments (PCCI) in patients with B-cell non-Hodgkin lymphoma (NHL), we used objective and subjective measures of cognitive functions in combination with serum parameters and neuroelectric recordings. Self-perceived status of cognition, fatigue and emotional functioning were reduced in patients (n = 30) compared to healthy controls (n = 10). Cognitive performance was impaired in patients with NHL compared to controls and a norm sample (n = 1179). PCCI was more severe in patients treated with rituximab and bendamustine (BR) than in patients who received R in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) polychemotherapy (R-CHOP). Individual alpha peak frequency and serum brain-derived neurotrophic factor (BDNF) levels in patients with NHL correlated with accuracy in the objective cognition test. Higher serum interleukin-6 (IL-6) concentrations were associated with higher fatigue levels. Patients with NHL and especially those who were treated with BR were affected by PCCI. BDNF and IL-6 might be involved in the pathogenesis of PCCI and fatigue.

Introduction: Physical activity is associated with decreased cancer (recurrence) risk and a reduction in treatment-specific side effects. Exercise modulates cytokine expression and shows beneficial effects on cancer patients' immune system. We investigated the following: (i) whether Non-Hodgkin-Lymphoma patients have increased serum macrophage migration inhibiting factor (MIF) and Interleukin-6 (IL-6) levels after immunochemotherapy; (ii) whether physical activity influences cytokine serum levels; and (iii) whether serum cytokine levels are associated with histone modifications in tumor-competitive immune cells. Methods: Thirty patients and 10 healthy controls were randomised into an intervention and a control group. Participants of the intervention group exercised once for 30 min at moderate intensity on a bicycle ergometer. Blood samples were collected twice, before and after the intervention. MIF and IL-6 serum concentrations were detected by ELISA. Natural killer cells and CD8(+) T-lymphocytes were isolated by magnetic labeled cell sorting. Isolated cells were stained and analyzed for global histone acetylation at histone 4, lysine 5 and histone three, lysine 9. Results: Patients showed higher serum MIF and IL-6 baseline levels, and reduced NK-cell histone acetylation, indicating a reduced transcriptional activity of tumor-competitive lymphocytes. Changes in MIF correlated with altered NK-cell histone acetylation, leading to the hypothesis that MIF impacts NK-cells via epigenetic modifications. Further, the exercise intervention was associated with an increase in IL-6 and CD8(+) T-lymphocyte histone acetylation. Conclusions: We conclude that exercise induces changes in cytokine levels, thereby possibly affecting epigenetic patterns and activity of tumor-competitive lymphocytes.

Introduction: Physical activity is associated with decreased cancer (recurrence) risk and a reduction in treatment-specific side effects. Exercise modulates cytokine expression and shows beneficial effects on cancer patients' immune system. We investigated the following: (i) whether Non-Hodgkin-Lymphoma patients have increased serum macrophage migration inhibiting factor (MIF) and Interleukin-6 (IL-6) levels after immunochemotherapy; (ii) whether physical activity influences cytokine serum levels; and (iii) whether serum cytokine levels are associated with histone modifications in tumor-competitive immune cells. Methods: Thirty patients and 10 healthy controls were randomised into an intervention and a control group. Participants of the intervention group exercised once for 30 min at moderate intensity on a bicycle ergometer. Blood samples were collected twice, before and after the intervention. MIF and IL-6 serum concentrations were detected by ELISA. Natural killer cells and CD8(+) T-lymphocytes were isolated by magnetic labeled cell sorting. Isolated cells were stained and analyzed for global histone acetylation at histone 4, lysine 5 and histone three, lysine 9. Results: Patients showed higher serum MIF and IL-6 baseline levels, and reduced NK-cell histone acetylation, indicating a reduced transcriptional activity of tumor-competitive lymphocytes. Changes in MIF correlated with altered NK-cell histone acetylation, leading to the hypothesis that MIF impacts NK-cells via epigenetic modifications. Further, the exercise intervention was associated with an increase in IL-6 and CD8(+) T-lymphocyte histone acetylation. Conclusions: We conclude that exercise induces changes in cytokine levels, thereby possibly affecting epigenetic patterns and activity of tumor-competitive lymphocytes.

Besides the genetic aberrations the interaction between the tumor cell and its microenvironment plays an important role in the leukemogenesis of chronic lymphocytic leukemia (CLL). Stimulation via extracellular factors is important for the survival of the CLL cell, since without this the CLL cell is driven into apoptosis when taken out of its micromilieu. Preliminary analyses showed that Macrophage Migration Inhibitory Factor (MIF), a chemokine with pro-inflammatory properties, is overexpressed in CLL. As MIF exerts regulatory control on cellular growth, -differentiation and apoptosis, this work tests the hypothesis whether MIF has a contribution in the pathomechanism of CLL development. To this end, we used the Eu-T-cell leukemia 1 (TCL1) mouse model (Bichi et al., 2002) in which B-cell specific overexpression of TCL1 leads to accumulation and organ infiltration by CD5+IgM+ mature B cells. The transgenic mice develop a CLL-like disease, which is manifested by leukemia, lymphadenopathy, hepatosplenomegaly, bone marrow infiltration as well as premature death after 8 to 15 months. The impact of MIF is tested in vivo by breeding the TCL1+/+ mouse to the MIF-/- mouse (Fingerle-Rowson et al., 2003). In this work, TCL1+/wt MIF+/+ and TCL1+/wt MIF-/- mice were compared with each other regarding the rate of leukemia development, tumor burden, hematopathological alterations, overall survival, cytogenetic changes as well as proliferative capacity and apoptosis. The known MIF cell surface receptors CD74/CD44 and CXCR2 are also expressed on the murine B cells. TCL1+/wt MIF+/+ mice show already in the pre-leukemic phase a higher number of CD5+IgM+ cells, and the development of a peripheral leukemia starts about three months earlier in TCL1+/wt MIF+/+ mice compared to TCL1+/wt MF-/- animals (p = 0.02). At the age of 12 months, organs like liver and spleen are infiltrated to a higher degree by small, mature and malignant B lymphocytes in the TCL1+/wt MIF+/+ than in the MIF-deficie

Besides the genetic aberrations the interaction between the tumor cell and its microenvironment plays an important role in the leukemogenesis of chronic lymphocytic leukemia (CLL). Stimulation via extracellular factors is important for the survival of the CLL cell, since without this the CLL cell is driven into apoptosis when taken out of its micromilieu. Preliminary analyses showed that Macrophage Migration Inhibitory Factor (MIF), a chemokine with pro-inflammatory properties, is overexpressed in CLL. As MIF exerts regulatory control on cellular growth, -differentiation and apoptosis, this work tests the hypothesis whether MIF has a contribution in the pathomechanism of CLL development. To this end, we used the Eu-T-cell leukemia 1 (TCL1) mouse model (Bichi et al., 2002) in which B-cell specific overexpression of TCL1 leads to accumulation and organ infiltration by CD5+IgM+ mature B cells. The transgenic mice develop a CLL-like disease, which is manifested by leukemia, lymphadenopathy, hepatosplenomegaly, bone marrow infiltration as well as premature death after 8 to 15 months. The impact of MIF is tested in vivo by breeding the TCL1+/+ mouse to the MIF-/- mouse (Fingerle-Rowson et al., 2003). In this work, TCL1+/wt MIF+/+ and TCL1+/wt MIF-/- mice were compared with each other regarding the rate of leukemia development, tumor burden, hematopathological alterations, overall survival, cytogenetic changes as well as proliferative capacity and apoptosis. The known MIF cell surface receptors CD74/CD44 and CXCR2 are also expressed on the murine B cells. TCL1+/wt MIF+/+ mice show already in the pre-leukemic phase a higher number of CD5+IgM+ cells, and the development of a peripheral leukemia starts about three months earlier in TCL1+/wt MIF+/+ mice compared to TCL1+/wt MF-/- animals (p = 0.02). At the age of 12 months, organs like liver and spleen are infiltrated to a higher degree by small, mature and malignant B lymphocytes in the TCL1+/wt MIF+/+ than in the MIF-deficie