scholarly journals Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia

2016 ◽  
Vol 64 (3) ◽  
pp. 740-744 ◽  
Author(s):  
Olivia L Francis ◽  
Terry-Ann M Milford ◽  
Cornelia Beldiman ◽  
Kimberly J Payne
Keyword(s):  
Precision Medicine ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Fine Tuning ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Preclinical Models ◽  
Species Activity ◽  
Pdx Models

Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches–targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.

scholarly journals BLNK suppresses pre–B-cell leukemogenesis through inhibition of JAK3

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1483-1492 ◽  
Author(s):  
Joji Nakayama ◽  
Mutsumi Yamamoto ◽  
Katsuhiko Hayashi ◽  
Hitoshi Satoh ◽  
Kenji Bundo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Leukemia Cells ◽  
Cell Leukemia ◽  
Cycle Arrest ◽  
B Cell Leukemia

Abstract Pre–B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre–B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre–B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK−/− mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27kip1 expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27kip1 induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7–dependent proliferation and survival of pre–B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre–B-cell leukemia.

scholarly journals PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3609-3617 ◽  
Author(s):  
Jinjun Dang ◽  
Lei Wei ◽  
Jeroen de Ridder ◽  
Xiaoping Su ◽  
Alistair G. Rust ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Genetic Alteration ◽  
Human Leukemia ◽  
Key Points ◽  
Leukemia Development ◽  
Common Target ◽  
Mouse Mutagenesis

Key Points Heterozygous alterations of Pax5, the most common target of genetic alteration in ALL, promote ALL in mouse mutagenesis models. Leukemia development is accompanied by the acquisition of genetic alterations commonly observed in human leukemia.

scholarly journals Inducible transgene expression in PDX models in vivo identifies KLF4 as therapeutic target for B-ALL

2019 ◽  
Author(s):  
Wen-Hsin Liu ◽  
Paulina Mrozek-Gorska ◽  
Tobias Herold ◽  
Larissa Schwarzkopf ◽  
Dagmar Pich ◽  
...  
Keyword(s):  
Residual Disease ◽  
Therapeutic Option ◽  
Lymphoblastic Leukemia ◽  
Clinical Model ◽  
Novel Technique ◽  
Pdx Model ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Disease Stages ◽  
Pdx Models

Clinic-close methods are not available that prioritize and validate potential therapeutic targets in individual tumors from the vast bulk of descriptive expression data. We developed a novel technique to express transgenes in established patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive pre-clinical in vivo trials, we found that re-expression of wild type KLF4 reduced leukemia load in PDX models of B-ALL, with strongest effects after conventional chemotherapy at minimal residual disease (MRD). A non-functional KLF4 mutant had no effect in this model. Re-expressing KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. Of major translational relevance, Azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced Azacitidine-induced cell death, suggesting that Azacitidine can regulate KLF4 re-expression. These results support applying Azacitidine in patients with B-ALL to regulated KLF4 as a therapeutic option. Taken together, our novel technique allows studying the function of dysregulated genes in a highly clinic-related, translational context and testing clinically applicable drugs in a relevant pre-clinical model.

scholarly journals Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects

2011 ◽  
Vol 35 (6) ◽  
pp. 800-807 ◽  
Author(s):  
Johan Jansson ◽  
Yu-Chiao Hsu ◽  
Igor I. Kuzin ◽  
Andrew Campbell ◽  
Craig A. Mullen
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Combination Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells

scholarly journals In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2817-2828 ◽  
Author(s):  
FM Uckun ◽  
CF Stewart ◽  
G Reaman ◽  
LM Chelstrom ◽  
J Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Topoisomerase I ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Water Soluble ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
B Lineage

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.

scholarly journals In Vitro and In Vivo Apoptosis-Inducing Antileukemic Effects of Mucuna macrocarpa Stem Extract on HL-60 Human Leukemia Cells

2010 ◽  
Vol 9 (3) ◽  
pp. 298-308 ◽  
Author(s):  
Kuan-Hung Lu ◽  
Yuh-Fang Chang ◽  
Pen-Hui Yin ◽  
Ting-Ting Chen ◽  
Yu-Ling Ho ◽  
...  
Keyword(s):  
Leukemia Cells ◽  
Human Leukemia ◽  
Human Leukemia Cells ◽  
Stem Extract

scholarly journals Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Duohui Jing ◽  
Vivek A. Bhadri ◽  
Dominik Beck ◽  
Julie A. I. Thoms ◽  
Nurul A. Yakob ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Intronic Region ◽  
Key Points ◽  
Pediatric All ◽  
Induced Apoptosis

Key Points The glucocorticoid receptor coordinately regulates the antiapoptotic BCL2 and proapoptotic BIM genes in pediatric ALL cells in vivo. GR binding at a novel intronic region is associated with BIM transcription and dexamethasone sensitivity in pediatric ALL cells in vivo.

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