Strong concordance between RNA structural and single nucleotide variants identified via next generation sequencing techniques in primary pediatric leukemia and patient-derived xenograft samples

Barwe, Sonali P.; Gopalakrisnapillai, Anilkumar; Mahajan, Nitin; Druley, Todd E.; Kolb, E. Anders; Crowgey, Erin L.

doi:10.5808/gi.2020.18.1.e6

Cited by 2 publications

(2 citation statements)

References 33 publications

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“…We have developed and characterized disseminated PDX models of pediatric AML with varying cytogenetic profiles using AML cells from patients treated at the Nemours Children’s Hospital [ 18 , 19 ]. The mouse passaged pediatric AML PDX lines used in this study ( n = 6) were generated using primary patient samples.…”

Section: Methodsmentioning

confidence: 99%

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

Barwe

Huang

Kolb

et al. 2022

JCM

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Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.

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Section: Methodsmentioning

confidence: 99%

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

Barwe

Huang

Kolb

et al. 2022

JCM

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“…The PDX lines NTPL-60, NTPL-146, NTPL-301, NTPL-377, NTPL-477, and NTPL-511 were generated and characterized as previously described [ 19 , 20 ]. PDX lines CBAM-44728-V1 and CBAM-68552-V1 (referred to as DF-5 and DF-2, respectively) were procured from Dana Farber Cancer Institute PRoXe depository [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia

Barwe

Kisielewski

Bonvini

et al. 2022

JCM

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Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 × CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.

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Strong concordance between RNA structural and single nucleotide variants identified via next generation sequencing techniques in primary pediatric leukemia and patient-derived xenograft samples

Cited by 2 publications

References 33 publications

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia

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