Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response.

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes.

Purpose: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.

Experimental Design: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.

Results: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL).

Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1.

Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs.

Targeted inhibition of CD47-SIRPα requires Fc-FcγR interactions to maximize activity in T-cell lymphomas.

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (MHC) class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I.

Effect of carbonate anion on cytochrome P450 2D6-mediated metabolism in vitro: the potential role of multiple oxygenating species.

Studies were designed to investigate various anions and their effects on cytochrome P450 2D6-mediated metabolism in vitro. Incubations were initially performed in buffered phosphate, carbonate, sulfate, and acetate solutions (50mM, pH 7.4), with CYP2D6 substrates dextromethorphan, 7-methoxy-4-(aminomethyl)-coumarin (MAMC), (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(-)-OSU6162], and amitriptyline.