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

التفاصيل البيبلوغرافية
العنوان:	Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.
المؤلفون:	Winter PS; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Ramseier ML; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Navia AW; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Saksena S; Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA.; Computational and Systems Biology Program, MIT, Cambridge, MA, USA., Strouf H; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Senhaji N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., DenAdel A; Center for Computational Molecular Biology, Brown University, Providence, RI, USA.; Department of Biostatistics, Brown University, Providence, RI, USA., Mirza M; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., An HH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Bilal L; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Dennis P; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Leahy CS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Shigemori K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Galves-Reyes J; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Zhang Y; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Department of Biological Engineering, MIT, Cambridge, MA, USA., Powers F; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Mulugeta N; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Gupta AJ; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Calistri N; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Van Scoyk A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Jones K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Liu H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Stevenson KE; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA USA., Ren S; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA USA., Luskin MR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Couturier CP; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Amini AP; Microsoft Research, Cambridge, MA, USA., Raghavan S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Kimmerling RJ; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Stevens MM; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA., Crawford L; Center for Computational Molecular Biology, Brown University, Providence, RI, USA.; Department of Biostatistics, Brown University, Providence, RI, USA.; Microsoft Research, Cambridge, MA, USA., Weinstock DM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Current Address: Merck and Co., Rahway, NJ, USA., Manalis SR; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biological Engineering, MIT, Cambridge, MA, USA., Shalek AK; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.; Institute for Medical Engineering & Science, MIT, Cambridge, MA, USA.; Department of Chemistry, MIT, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Murakami MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.
المصدر:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 10. Date of Electronic Publication: 2024 Jun 10.
نوع المنشور:	Journal Article; Preprint
اللغة:	English
بيانات الدورية:	Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص:	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.
معلومات مُعتمدة:	P30 CA014051 United States CA NCI NIH HHS; K08 CA212252 United States CA NCI NIH HHS; R35 CA231958 United States CA NCI NIH HHS; K12 HL141953 United States HL NHLBI NIH HHS; U54 CA217377 United States CA NCI NIH HHS
فهرسة مساهمة:	Keywords: Biophysical Measurements; Cell State; Minimal Residual Disease; Mutations; Ph+ B cell acute lymphoblastic leukemia
تواريخ الأحداث:	Date Created: 20240625 Latest Revision: 20240701
رمز التحديث:	20240701
مُعرف محوري في PubMed:	PMC11195125
DOI:	10.1101/2024.06.06.597767
PMID:	38915726
قاعدة البيانات:	MEDLINE

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تدمد:	2692-8205
DOI:	10.1101/2024.06.06.597767