PXD068585-1

PXD068585 is an original dataset announced via ProteomeXchange.

Title	Kinome profiling of venetoclax-resistant wild type and NRAS-G12C MOLM-14 cells
Description	Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. Kinome profiling of Molm14 cells, both NRAS WT and NRAS G12C, both treatment-naive and venetoclax resistant, additionally shows RAS upregulation with venetoclax resistance. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.
HostingRepository	PRIDE
AnnounceDate	2026-06-15
AnnouncementXML	Submission_2026-06-14_16:43:42.260.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christine Berryhill
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-19 10:49:51	ID requested
⏵ 1	2026-06-14 16:43:43	announced

Kennedy VE, Peretz CAC, Walia A, Chyla B, Sun Y, Hill JE, Tran E, Koh AD, Ferng TT, Pintar S, Jones M, Popescu B, Lomeli I, Chehab F, Murad N, John A, Roy RP, Olshen AB, Berryhill CA, Davis C, Angus SP, Rivera JM, Meshulam A, Stieglitz E, Joshi SK, Traer E, Dail M, Hamidi H, Altman JK, Daver NG, Levis MJ, McCloskey J, Perl AE, Smith CC, Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy. Blood, ():(2026) [pubmed]

10.1182/blood.2025032466;

submitter keyword: venetoclax, gilteritinib,Kinase, inhibitor, bead, AML

Catherine Smith
contact affiliation	UCSF
contact email	catherine.smith@ucsf.edu
lab head
Christine Berryhill
contact affiliation	Indiana University School of Medicine
contact email	causherm@iu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD068585

PRIDE project URI

• PRIDE
  1. PXD068585
     1. Label: PRIDE project
     2. Name: Kinome profiling of venetoclax-resistant wild type and NRAS-G12C MOLM-14 cells