52 research outputs found
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Subclonal heterogeneity sheds light on the transformation trajectory in IGLV3-21R110 chronic lymphocytic leukemia.
Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups
Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires
robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic
subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic
CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation.
Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows
engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated
NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac (NOG) mice in contrast to C.Cg-Rag2tm1Fwa-/-
Il2rgtm1Sug/JicTac
(BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells
were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with
low fractions of autologous T cells (2%â4%). CLL transplanted NOG mice (24 different patients)
developed CLL pseudofollicles in the spleen, which increased over 4â6 weeks, and were then limited
by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our
model, and recapitulated treatment responses seen in patients. In conclusion, we developed an
easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without
humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to
explore novel drug candidates
FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC)
thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a
multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is
approved for advanced radioiodine refractory thyroid carcinoma, but response to single
agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor
pembrolizumab (PEM) are promising.
Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples
diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1
expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4
mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization.
Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls.
Disease specific survival (DSS) was the primary outcome variable.
Results: PD-L1 TPSâ„50% was observed in 42% of ATC and 26% of PDTC specimens.
Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%;
p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression â€5%.
FGFR mRNA expression was generally low in all samples but combined FGFR1-4
expression was significantly higher in PDTC and ATC compared to NT (each p<0.001).
No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.
Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a
subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR
expression is low thyroid tumor cells. The clinically observed synergism of PEM with
LEN may be caused by immune modulation
Spleen Tyrosine Kinase Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia
Dissection of PIM serine/threonine kinases in FLT3-ITDâinduced leukemogenesis reveals PIM1 as regulator of CXCL12âCXCR4-mediated homing and migration
FLT3-ITDâmediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITDâmediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients, whereas lack of PIM2 induction did not interfere with FLT3-ITDâinduced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12âCXCR4 signaling. Through small interfering RNAâmediated knockdown, chemical inhibition, expression of a dominant-negative mutant, and/or reexpression in knockout cells, we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells toward a CXCL12 gradient. Purified PIM1 led to the phosphorylation of serine 339 in the CXCR4 intracellular domain in vitro, a site known to be essential for normal receptor recycling. In primary leukemic blasts, high levels of surface CXCR4 were associated with increased PIM1 expression, and this could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is important for homing and migration of hematopoietic cells through modification of CXCR4. Because CXCR4 also regulates homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their antitumor effects in part by interfering with interactions with the microenvironment
Automatic covariance pattern analysis outperforms visual reading of 18 Fâfluorodeoxyglucoseâpositron emission tomography (FDGâPET) in variant progressive supranuclear palsy
Background: To date, studies on positron emission tomography (PET) with F-18-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). Objectives: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. Results: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. Conclusions: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. (C) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Optimized xenograft protocol for chronic lymphocytic leukemia results in high engraftment efficiency for All CLL subgroups
Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-PrkdcIl2rg/JicTac (NOG) mice in contrast to C.Cg-Rag2Il2rg/JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%-4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4-6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates
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