Genomics and drug profiling of fatal TCF3-HLF−positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options

Abstract

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.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…In addition, complete response was detected when treating the T-VHR-03 case in mice with high leukemia burden (75% engraftment; supplemental Figure 8). We recently reported similar venetoclax efficacy in 3 TCF3-HLF ALL patients in vivo 35 ; comparable correlations were obtained in 2 patients with TCF3-HLF-or MLL-rearranged ALL ( Figure 5A). For all tested cases, venetoclax-induced delays in in vivo leukemia progression correlated with in vitro responses (Spearman r 5 -0.86; P , .05; Figure 5B).…”

“…We also included samples from TCF3-HLF-and TCF3-PBX1-positive ALL subtypes for which we recently reported a strong conservation of the genomic landscape in PDXs. 35 To evaluate the potential of this ex vivo platform, we profiled 24 T-ALL and 44 BCP-ALL PDXs derived from pretreatment diagnostic samples (ALL-BFM 2000 study 36 ; Figure 2). For each drug, we used 8 doses optimized from an initial 5-point screen (supplemental Table 4).…”

“…The profiles that we detected for venetoclax, 30 which was recently approved for treatment of chronic lymphocytic leukemia, illustrate the type of information that could be used to improve patient selection in early clinical trials. We show that a relatively large proportion of BCP-ALL patients may respond to venetoclax, including very high-risk subtypes such as TCF3-HLF- 35 and MLL-AF4-positive ALL. Our findings are confirmed independently by others who showed strong venetoclax activity in MLL-rearranged ALL.…”

“…We and others 16,18 have demonstrated the use of drug profiling for identifying phenotypes that are responsive to new therapeutic agents. We have identified recurrent ALL patients who are highly sensitive to triggering RIP1-dependent cell death with SMAC mimetics 37 or to BCL2 inhibition in BCP-ALL subsets, including TCF3-HLF ALL 35 and T-ALL subsets. Moreover, we discovered a subgroup in T-ALL that is highly sensitive to dasatinib, which should be further evaluated first in patients with highly drugresistant and refractory disease.…”

Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia

“…63 Our study included 1 such xenograft (ALL-7), which achieved a CR when exposed to venetoclax, progression delay of 27 days, and T/C value of 5.7. A similar response was previously observed when navitoclax was tested against ALL-7 in vivo.…”