The Clinical Spectrum of Hepatic Manifestations in Chronic Lymphocytic Leukemia

Kreiniz, Natalia; Katz, Ofrat Beyar; Polliack, Aaron; Tadmor, Tamar

doi:10.1016/j.clml.2017.07.008

Cited by 12 publications

(6 citation statements)

References 66 publications

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“…The extent of organ infiltration by leukemic cells was measured in spleen, bone marrow and lymph nodes from Eμ-TCL1 and Eμ-TCL1/p66Shc −/− mice with ~60% leukemic cells in peripheral blood. The analysis was extended to liver and lung, as infiltration in these organs has been documented in CLL, 21,22 as well as to the peritoneal infiltrate.…”

Section: Resultsmentioning

confidence: 99%

“…p66Shc deficiency also results in a striking extranodal accumulation of leukemic cells, with a preference for liver and lung, the most frequent extranodal target sites in CLL. 21,22 The ROS-related ability of p66Shc to modulate the expression and function of CCR2 and CXCR3, which drive neoplastic B-cell homing to liver and lung where the respective ligands are expressed, 42,43 may account for the enhanced ability of leukemic Eμ-TCL1/p66Shc −/− cells to colonize these organs. Interestingly, CCR2 and CXCR3 are overexpressed in CLL cells (as shown in this study and reported by Trentin et al .…”

Section: Discussionmentioning

confidence: 99%

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p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

et al. 2019

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The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Eμ-TCL1/p66Shc−/− mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Eμ-TCL1 mice. Eμ-TCL1/p66Shc−/− mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells’ level of p66Shc expression. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

et al. 2019

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“…Additionally, CLL-conditioned stromal cells overexpress the CCR2 (CCL2) and CXCR3 (CXCL9/-10/-11) ligands which attract immune cells to liver and spleen, 33,34 where CLL cells infiltrate at advanced disease stages. 35,36 Expression of the CXCR4 ligand CXCL12, which promotes CLL cell homing and survival, 28 is not significantly upregulated in stromal cells, suggesting that the increase in surface CXCR4 on CLL cells 4,31 is sufficient for their effective homing to SLOs.…”

Section: Discussionmentioning

confidence: 99%

Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment

Patrussi

Manganaro

Capitani

et al. 2021

Blood

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The stromal microenvironment is central to chronic lymphocytic leukemia (CLL) pathogenesis. How leukemic cells condition the stroma to enhance its chemoattractant properties remains elusive. Here we show that mouse and human CLL cells promote the contact-independent stromal expression of homing chemokines. This function was strongly enhanced in leukemic cells from Em-TCL1 mice lacking the pro-oxidant p66Shc adaptor, which develop an aggressive disease with organ infiltration. We identified Interleukin (IL) -9 as the soluble factor, negatively modulated by p66Shc, responsible for the chemokine-elevating activity of leukemic cells on stromal cells. IL-9 blockade in Em-TCL1/p66Shc-/- mice resulted in a decrease in the nodal expression of homing chemokines, which correlated with decreased leukemic cell invasiveness. IL-9 levels were found to inversely correlate with residual p66Shc in the p66Shc-deficient human CLL cells (n=52 patients). p66Shc reconstitution in CLL cells normalized IL-9 expression and neutralized their chemokine-elevating activity. Notably, high IL-9 expression in CLL cells directly correlates with lymphadenopathy, liver infiltration, disease severity and overall survival, emerging as an independent predictor of disease outcome. Our results demonstrate that IL-9 modulates the chemokine landscape in the stroma, and that p66Shc, by regulating IL-9 expression, tunes the ability of leukemic cells to shape the microenvironment, thereby contributing to CLL pathogenesis.

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“…In intra-abdominal CLL, unifocal or multifocal lymphadenopathy or diffuse soft tissue infiltration throughout the mesentery, retroperitoneum and solid organs might be seen [4]. Numerous enlarged lymph nodes or organ infiltration can lead to liver failure, cholecystitis, peritonitis, pancreatico-biliary obstruction or thrombosis of surrounding mesenteric arteries and veins [5]. In rare cases, the leukemic cells can possibly infiltrate the gastrointestinal tract and cause ulcer, polypoid lesions and clinical pictures mimicking malabsorption disorders or chronic inflammatory bowel disease [6–8].…”

Section: Discussionmentioning

confidence: 99%

When abdominal pain knocks the door: an unusual presentation of chronic lymphocytic leukemia

Etık

Suna

Börcek

et al. 2019

Oxford Medical Case Reports

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The Clinical Spectrum of Hepatic Manifestations in Chronic Lymphocytic Leukemia

Cited by 12 publications

References 66 publications

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment

When abdominal pain knocks the door: an unusual presentation of chronic lymphocytic leukemia

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