Differential adhesion pattern of B cell chronic lymphocytic leukemia cells

Behr, Susanne; Korinth, Dirk; Schriever, Folke

doi:10.1038/sj.leu.2400883

Cited by 27 publications

(23 citation statements)

References 51 publications

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“…Previous studies identified several molecules that may mediate CD19-induced homotypic aggregation in B cells, including CD21, CD23, CD62L, and b 2 integrin (27)(28)(29). We found surface expression of all of these molecules on CLL cells, as previously reported (data not shown).…”

Section: Characterization Of the Cd19-responsive Subpopulation Of Cllsupporting

confidence: 77%

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Herishanu

Kay

Dezorella

et al. 2013

The Journal of Immunology

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Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19–signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow–derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.

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Section: Characterization Of the Cd19-responsive Subpopulation Of Cllsupporting

confidence: 77%

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Herishanu

Kay

Dezorella

et al. 2013

The Journal of Immunology

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“…For the patients, to avoid further blood loss, allogeneic lymphocytes were used for the assay. Previous reports confirmed the validity of using HLAindependently allogeneic B or T cells for functionally relevant adhesion assays [6][7][8]. As determined by flow cytometry, activated T cell preparations that were used in the adhesion assay consisted of G 86% CD3-positive cells, coexpressing CD4 (53±16%), CD8 (54±15%), CD45RA (26±15%) and CD45RO (79±17%).…”

Section: Activated T Lymphocytes Bind To Tumor Stroma But Not To Malimentioning

confidence: 62%

Activated T lymphocytes bindin situ to stromal tissue of colon carcinoma but lack adhesion to tumor cells

2001

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“…on May 9, 2018. by guest www.bloodjournal.org From has been shown previously that CD40 stimulation induces homotypic adhesion in normal B cells, 34 although this was not confirmed for CLL cells. 35 Figure 3 shows mild HA of CLL cells after CD40 stimulation, which was strongly increased by GA101 or GXL. To determine whether the processes of HA and cell death were functionally linked, cells were treated with cytoD, an agent that inhibits actin polymerization.…”

Section: Cd40 Stimulation Sensitizes Cll Cells To Ga101 5181mentioning

confidence: 99%

“…35 Figure 3 shows mild HA of CLL cells after CD40 stimulation, which was strongly increased by GA101 or GXL. To determine whether the processes of HA and cell death were functionally linked, cells were treated with cytoD, an agent that inhibits actin polymerization.…”

Section: Org Frommentioning

confidence: 99%

CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101

Jak¹,

Bochove²,

Reits

et al. 2011

Blood

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Sensitivity of chronic lymphocytic leukemia (CLL) cells to anti-CD20 mAbs is low and, therefore, the efficacy of monotherapy with current anti-CD20 mAbs is limited. At present, it is not known whether sensitivity of CLL cells to CD20 mAbs is modulated by microenvironmental stimuli. We have shown previously that in vitro CD40 stimulation of peripheral bloodderived CLL cells results in resistance to cytotoxic drugs. In the present study, we show that, in contrast, CD40 stimulation sensitizes CLL cells to the recently described novel type II anti-CD20 mAb GA101. Cell death occurred without crosslinking of GA101 and involved a lysosomedependent mechanism. Combining GA101 with various cytotoxic drugs resulted in additive cell death, not only in CD40-stimulated CLL cells, but also in p53-dysfunctional CLL cells. Our findings indicate that GA101 has efficacy against chemoresistant CLL, and provide a rationale for combining cytotoxic drugs with anti-CD20 mAbs. (Blood. 2011;118(19): 5178-5188) IntroductionAlthough treatment results for chronic lymphocytic leukemia (CLL) have improved considerably over the last decade, a curative drug regimen is still lacking. Similar to other B-cell malignancies such as follicular lymphoma and multiple myeloma, in CLL, the interaction of the malignant cells with their microenvironment in the lymph nodes, spleen, and possibly BM has been shown to play an important role in the biology of the disease. 1 We and others have previously shown that in vitro CD40 stimulation of CLL cells can to a certain extent mimic the lymph node environment and results in the induction of resistance of the CLL cells to cytotoxic drugs such as fludarabine, chlorambucil, bortezomib, and roscovitine. [2][3][4][5][6] These microenvironmental niches might be an important localization of minimal residual disease and form the basis for the relapses characterizing this disease. 1,[3][4][5]7,8 Moreover, after sequential treatments, selection of p53 dysfunctional clones occurs in up to 50% of patients, 9,10 which also results in chemoresistance. Therefore, there is a need for new treatments that circumvent microenvironmental chemoresistance and act independently of p53, possibly including anti-CD20 mAb-containing regimens. 11,12 However, sensitivity of CLL cells to anti-CD20 mAbs in vitro is low and monotherapy with conventional doses of the type I anti-CD20 mAb rituximab has only limited efficacy in CLL. Because of rituximab resistance or unresponsiveness, more potent anti-CD20 mAbs are currently being sought. Two types of anti-CD20 mAbs have been described. A prime difference is that, in contrast to type I anti-CD20 mAbs, type II mAbs are unable to translocate CD20 into lipid rafts or to evoke Ca 2ϩ flux. [13][14][15][16] Ofatumumab, a second-generation type I anti-CD20 mAb seems promising for the treatment of CLL, 17 although large amounts seem to be required. GA101 is a novel glycoengineered type II anti-CD20 mAb. Compared with rituximab, GA101 has enhanced direct cell death-inducing capacity and improved Ab-depende...

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Differential adhesion pattern of B cell chronic lymphocytic leukemia cells

Cited by 27 publications

References 51 publications

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Activated T lymphocytes bindin situ to stromal tissue of colon carcinoma but lack adhesion to tumor cells

CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101

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