1. Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.
- Author
-
Winter PS, Ramseier ML, Navia AW, Saksena S, Strouf H, Senhaji N, DenAdel A, Mirza M, An HH, Bilal L, Dennis P, Leahy CS, Shigemori K, Galves-Reyes J, Zhang Y, Powers F, Mulugeta N, Gupta AJ, Calistri N, Van Scoyk A, Jones K, Liu H, Stevenson KE, Ren S, Luskin MR, Couturier CP, Amini AP, Raghavan S, Kimmerling RJ, Stevens MM, Crawford L, Weinstock DM, Manalis SR, Shalek AK, and Murakami MA
- Abstract
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. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples., Competing Interests: DECLARATION OF INTERESTS S.R.M., R.J.K., M.M.S., and D.M.W. disclose equity ownership in Travera. A.K.S. reports compensation for consulting and/or SAB membership from Honeycomb Biotechnologies, Cellarity, Bio-Rad Laboratories, Fog Pharma, Passkey Therapeutics, Ochre Bio, Relation Therapeutics, IntrECate biotherapeutics, and Dahlia Biosciences unrelated to this work. P.S.W receives research funding from Microsoft. S.R. holds equity in Amgen and receives research funding from Microsoft. D.M.W. is an employee of Merck and Co., owns equity in Merck and Co., Bantam, Ajax, and Travera, received consulting fees from Astra Zeneca, Secura, Novartis, and Roche/Genentech, and received research support from Daiichi Sankyo, Astra Zeneca, Verastem, Abbvie, Novartis, Abcura, and Surface Oncology. P.S.W., A.K.S., M.A.M., S.R.M., and D.M.W. have filed a patent related to this work. Other authors – none.
- Published
- 2024
- Full Text
- View/download PDF