Publications

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a highly aggressive malignancy with an overall median survival of only 7 months.¹  In addition, only 38 patients with MEITL were identified from 4 institutes over a period of 19 years.²  These factors pose great challenges to better understanding and managing the disease. Therefore, there is a dire need to establish clinically relevant models to explore the efficacy of therapeutic targets to improve the management of MEITL.

Whole-genome sequencing (WGS) and whole-transcriptomics profiling were performed for 4 MEITL tumors (supplemental Table 1). Whole exome sequencing (WES) was performed for patient-derived xenograft (PDX) tumors. Details are described in the “Materials and methods” in the supplemental Materials. The human subject study was approved by the SingHealth Centralized Institutional Review Board (2004/407/F).

All experiments were approved by the SingHealth Institutional Animal Care and Use Committee. For the PDX model, fresh tumor tissue was minced and subcutaneously implanted in the flank of NSG mice. For the orthotopic model, minced tissue was intraperitoneally inoculated into the mice. The animal study was approved by the SingHealth Institutional Animal Care and Use Committee (2018/SHS/1423).

Dissociated cells were treated with drug combinations based on the orthogonal array composite design.³  A total of 12 drugs at 3 concentrations were interrogated, and of a total of more than 500 000 combinations, 155 were empirically tested. The correlation of treatment combination (input) and corresponding cell viability (output) was fitted into a second-order quadratic equation, generating ranked drug combinations and predicted cell viability. The details of the quadratic phenotypic optimization platform (QPOP) are described in previous publications.^4,5 

The rest of the “Materials and methods” are described in the supplemental Materials.

To elucidate the whole-genome profile of MEITL, we performed WGS on 4 MEITL tumors from separate cases and matched normal blood samples with an average depth of 68× and 59× (supplemental Table 2). An average of 1.52 somatic short variants per megabyte was called from each sample. Neither microsatellite instability nor hypermutation was detected. A total of 338 nonsilent protein-coding mutations (average, 84.5; range, 62-121; supplemental Table 3) were detected, and recurrent mutations were validated in CREBBP, STAT5B, SETD2, GNAI2, JAK3, and AXSL3 (Figure 1A), which are consistent with those in previous studies.^1,6,7