DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for mast-cell leukemia — screening already-approved drugs against its 26-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMast-cell leukemia maps to a 26-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedDasatinibApproved drugapprovedPonatinibApproved drug
Structures already discussed alongside mast-cell leukemia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of EphA4 kinase domain — Dasatinib has a real, experimentally solved structure in complex with this target (PDB 2Y6O, 1.543 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet 1n1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2Y6O · 1.543 Å · ligand Dasatinib (1N1). Experimental structure, not a prediction.
What the evidence adds up to
Mast cell leukemia is an extremely rare and aggressive haematologic malignancy with a poor prognosis and short survival. No standardised treatment guidelines have been established. A 2017 case report describes a 79-year-old woman whose diagnosis was made after atypical cells were seen on blood and bone marrow smears, representing more than 10% of blood nucleated cells and more than 20% of bone marrow nucleated cells. Immunophenotyping revealed a cell subset expressing CD117, CD2, and CD25, the hallmark of malignant mast cells. KIT gene sequencing in that patient showed the N822Y mutation in exon 17, not the more common KIT D816V mutation. The patient was initially treated with midostaurin, a tyrosine kinase inhibitor, but showed no therapeutic response, and was then switched to imatinib following the latest scientific recommendations at the time.
A 2008 study identified novel KIT transcripts in two patients with mast cell leukemia and two patients with systemic mastocytosis with an associated haematological disorder, but not in two patients with systemic mastocytosis alone. Similar novel KIT transcripts were also found in normal CD34+ cells from bone marrow and umbilical cord blood, suggesting altered KIT isoforms may be specific to the blast stage of haematopoietic precursors. The novel KIT proteins lacked several domains including the ATP binding site, and one was inactive in a functional test for autophosphorylation. That study underscored the importance of analysing entire protein encoding regions when studying KIT.
A 2014 study using murine and human models demonstrated that loss of function of TET2 cooperates with constitutively active KIT D816V to produce a more aggressive phenotype in a murine model of systemic mastocytosis when both mutations are present in progenitor cells. The authors exploited these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor. A 2025 literature review noted that current treatment of aggressive systemic mastocytosis and mast cell leukemia is unsatisfactory, and that increasing clinical awareness of mast cell leukemia aims to provide insights for clinicians in diagnosis and management.
What is still missing are prospective clinical trials large enough to establish standard treatment guidelines for mast cell leukemia, given its extreme rarity. The heterogeneity of KIT mutations — including D816V, N822Y, and novel transcripts — means that patient stratification by mutation type is needed before targeted therapies can be reliably tested. Funding for multi-centre collaborative studies and for the development of combination strategies targeting both KIT and epigenetic modifiers such as TET2 remains inadequate.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2013 · 44 citations · open access
Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V
AbstractPatients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and investigated whether ponatinib acts synergistically with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V(+)) and HMC-1.2 cells (KIT G560V(+)/KIT D816V(+)) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells.
Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis
AbstractSystemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.
Leukemia & lymphoma/Leukemia and lymphoma · 2008 · 12 citations
The identification and characterisation of novel<i>KIT</i>transcripts in aggressive mast cell malignancies and normal CD34+ cells
AbstractKIT mutations have been identified in several malignancies, including acute myeloid leukemia (AML) and systemic mastocytosis (SM). Mast cell leukemia (MCL) is the most aggressive mast cell neoplasm, but has not been well studied due to its rarity. We identified novel KIT transcripts in two patients with MCL and two patients with SM with an associated hematological disorder, but not from two patients with SM. Similar novel KIT transcripts were also observed in normal CD34+ cells from bone marrow and umbilical cord blood, suggesting that altered KIT isoforms may be specific to the blast stage of hematopoietic precursors. The novel KIT proteins lack several domains including the ATP binding site, and one was inactive in a functional test for autophosphorylation. Our discovery of novel KIT transcripts underscores the importance of analysing entire protein encoding regions when studying genes of interest.
Frontiers in Oncology · 2025 · 1 citations · open access
Mast cell leukemia: a rare case report and literature review
AbstractMast cell leukemia (MCL) is an extremely rare and aggressive hematologic malignancy, characterized by a poor prognosis and short survival. Currently, no standardized treatment guidelines have been established. This study presents the clinical data of a patient with primary MCL accompanied by C-findings, and analyzes the clinical features, diagnostic challenges, and therapeutic approaches for this disease through a comprehensive review of the relevant literature. Furthermore, the study discusses current perspectives on research developments in MCL. By increasing clinical awareness of MCL, this work aims to provide valuable insights and references for clinicians in the diagnosis and management of this challenging condition.
From the observation of atypical cells on blood smear to the diagnosis of mast cell leukemia: a case report in a 79 year old woman consulting for anemia
AbstractMast cell leukemia is an extremely rare disease, which belongs to the systemic mastocytosis group (WHO 2016). We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal. Unusual cells were seen on blood and bone marrow smears. They represent more than 10% of blood nucleated cells end more than 20% of the bone marrow nucleated cells. Bone marrow immunophenotyping was performed to characterize these cells. It revealed a cell subset expressing the surface antigens CD117, CD2 and CD25. This immunophenotypic profile is the hallmark of malignant mast cells. Then mast cell leukemia diagnosis could have been made and KIT gene sequencing highlighted the N822Y mutation in exon 17. The patient was initially treated with midostaurin, a tyrosine kinase inhibitor. Lack of therapeutic response and absence of the KIT D816V mutation led to switch to imatinib, following the latest scientific recommendations.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
