6 research outputs found
Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe
Ex vivo drug response profiling detects recurrent sensitivity patterns in drug resistant ALL
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide
important functional information to guide actionable target and biomarker discovery. We
provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL)
samples mostly from resistant disease in co-cultures on bone marrow stromal cells. Patientderived
xenografts retained the original pattern of mutations found in the matched patient
material. Stromal co-culture did not prevent leukemia cell cycle activity, while a specific
sensitivity profile to cell cycle related drugs identified samples with higher cell proliferation
both in vitro and in vivo as leukemia xenografts. In cases with refractory relapses, individual
patterns of marked drug resistance, but also exceptional responses to new agents of
immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active
below 10 nM in BCP-ALL subsets including MLL-AF4 and TCF3-HLF ALL, and in some TALLs,
predicting in vivo activity as a single agent and in combination with dexamethasone
and vincristine. Unexpected sensitivity to dasatinib with IC50 values below 20 nM was
detected in two independent T-ALL cohorts, which correlated with similar cytotoxic activity of
the SRC Inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory TALL
was treated with dasatinib based on drug profiling information and achieved a fivemonth
remission. Thus, drug profiling captures disease-relevant features and unexpected
sensitivity to relevant drugs, which warrants further exploration of this functional assay in the
context of clinical trials in order to develop drug repurposing strategies for patients with
urgent medical needs
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
TCF3-HLF-fusion positive acute lymphoblastic leukemia (ALL) is currently incurable. Employing an integrated approach, we uncovered distinct mutation, gene expression, and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. Recurrent intragenic deletions of PAX5 or VPREB1 were identified in constellation with TCF3-HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin towards a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics, but sensitivity towards glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease
Genomics and drug profiling of fatal TCF3-HLF\ue2 'positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
TCF3-HLF 12positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF 12positive and treatment-responsive TCF3-PBX1 12positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease