Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.
- MeSH
- akutní lymfatická leukemie * farmakoterapie MeSH
- amidohydrolasy terapeutické užití MeSH
- B-lymfocyty MeSH
- chemorezistence * genetika MeSH
- dítě MeSH
- GPI-vázané proteiny MeSH
- hematopoetické kmenové buňky MeSH
- lidé MeSH
- molekuly buněčné adheze MeSH
- prospektivní studie MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amidohydrolasy MeSH
- GPI-vázané proteiny MeSH
- molekuly buněčné adheze MeSH
- VNN2 protein, human MeSH Prohlížeč
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
- MeSH
- akutní lymfatická leukemie farmakoterapie patologie MeSH
- anthelmintika farmakologie terapeutické užití MeSH
- apoptóza účinky léků MeSH
- chemorezistence MeSH
- lidé MeSH
- myši SCID MeSH
- nádorové buňky kultivované MeSH
- nádorové mikroprostředí účinky léků MeSH
- přehodnocení terapeutických indikací léčivého přípravku * MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anthelmintika MeSH
- protinádorové látky MeSH
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive 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.
- MeSH
- aktivátorový protein specifický pro B-buňky genetika MeSH
- akutní lymfatická leukemie farmakoterapie genetika mortalita MeSH
- chemorezistence MeSH
- exprese genu MeSH
- fúzní onkogenní proteiny genetika metabolismus MeSH
- genetické asociační studie MeSH
- genomika MeSH
- inhibiční koncentrace 50 MeSH
- Kaplanův-Meierův odhad MeSH
- kohortové studie MeSH
- kokultivační techniky MeSH
- lidé MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- náhradní lehké řetězce imunoglobulinů genetika MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- sekvenční delece MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aktivátorový protein specifický pro B-buňky MeSH
- fúzní onkogenní proteiny MeSH
- náhradní lehké řetězce imunoglobulinů MeSH
- PAX5 protein, human MeSH Prohlížeč
- protinádorové látky MeSH
- TCF3-HLF fusion protein, human MeSH Prohlížeč
- VPREB1 protein, human MeSH Prohlížeč
