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
- antitumorózní látky farmakologie terapeutické užití 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
- sekvenční delece MeSH
- xenogenní modely - testy antitumorózní 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
