DeCure for Systemic Mastocytosis with Associated Clonal Hematological non-Mast-Cell Lineage Disease
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Systemic Mastocytosis with Associated Clonal Hematological non-Mast-Cell Lineage Disease — screening already-approved drugs against its 23-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSystemic Mastocytosis with Associated Clonal Hematological non-Mast-Cell Lineage Disease maps to a 23-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
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
tripartite motif containing 24 (TRIM24) — TRIM24 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet benzyloxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4YBM · 1.46 Å · ligand N-{6-[3-(benzyloxy)phenoxy]-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}-3,4-dimethoxybenzenesulfonamide (4BJ). Experimental structure, not a prediction.
What the evidence adds up to
Systemic mastocytosis with an associated clonal haematological non-mast cell lineage disease (SM-AHNMD) is recognised by the World Health Organization as a distinct subgroup of mastocytosis. In a review of approximately 30,000 bone marrow biopsy reports from a single centre between 1996 and 2009, SM was diagnosed in 30 biopsies (0.1%), and SM-AHNMD was found in 8 of those patients (27% of SM cases). The associated neoplasms in that series were myelodysplastic syndrome (3 cases), myelodysplastic/myeloproliferative neoplasm (2 cases, both chronic myelomonocytic leukaemia), acute myeloid leukaemia (1 case), marginal zone lymphoma (1 case), and plasma cell myeloma (1 case). Over 80% of SM-AHNMD cases in the literature involve disorders of myeloid cell lines; only 8 cases of SM associated with a plasma cell disorder had been reported as of 2016.
In the 8-patient case series, all patients presented with cytopenia, and two had monocytosis. Activating c-Kit D816V point mutation was detected in 3 of 4 patients tested. Cytogenetic abnormalities were identified in 3 of 4 cases, including t(8;21), t(3;5), isochromosome 14, deletion 5q, and trisomy 4. In 6 of the 8 patients, SM was diagnosed concurrently with the AHNMD, and the aberrant mast cell proliferation was observed only after complete histopathologic examination. Two patients had long-standing indolent or cutaneous mastocytosis prior to developing an AHNMD. All patients were managed according to standard treatment protocols for their AHNMD; the patient with AML and t(8;21) received daunorubicin and cytarabine induction chemotherapy and intrathecal methotrexate, achieving remission followed by multiple relapses. The authors note that unlike most patients with AML and t(8;21), this patient fared poorly with standard chemotherapy.
The clinical presentation of SM-AHNMD is extremely varied, and the diagnosis often poses a histopathologic challenge that can be missed. In the majority of cases, mastocytosis is not clinically suspected, and the patient's presentation is related to the associated non-mast cell lineage neoplasm. Symptoms related to mastocytosis are treated with antihistamines as needed. The prognostic relevance and therapeutic implications of detecting SM with another haematologic malignancy remain to be clarified. What is still missing are prospective studies with sufficient patient numbers to determine whether the presence of SM alters the expected response to standard AHNMD therapy, and whether targeted agents against mutated Kit protein could improve outcomes in this subgroup.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Acta Haematologica · 2005 · 53 citations
Clonality and Molecular Pathogenesis of Mastocytosis
AbstractMast cell is a hematopoietic lineage dependent on Kit signaling for growth, differentiation, and survival. Mast cells are found in excessive numbers in tissues in a heterogeneous group of disorders collectively known as mastocytosis. Last decade has witnessed important advancements in our understanding of the molecular pathology of mastocytosis. First, systemic mastocytosis has been found to be associated with activating codon 816 mutations of the c-kit gene. Second, this mutation was used as a tracking marker to elucidate the clonal nature of mastocytosis. These findings have resulted in consideration of systemic mastocytosis as a clonal neoplastic disorder of a hematopoietic progenitor cell. Improved knowledge of the mechanisms causing pathological mast cell growth will lead to the discovery of novel treatment options including drugs targeting the mutated Kit protein.
Advances in the understanding and clinical management of mastocytosis and clonal mast cell activation syndromes
AbstractClonal mast cell activation syndromes and indolent systemic mastocytosis without skin involvement are two emerging entities that sometimes might be clinically difficult to distinguish, and they involve a great challenge for the physician from both a diagnostic and a therapeutic point of view. Furthermore, final diagnosis of both entities requires a bone marrow study; it is recommended that this be done in reference centers. In this article, we address the current consensus and guidelines for the suspicion, diagnosis, classification, treatment, and management of these two entities.
Case Reports in Oncological Medicine · 2016 · 7 citations · open access
Systemic Mastocytosis with Smoldering Multiple Myeloma: Report of a Case
AbstractSystemic mastocytosis (SM) is a disease characterized by a clonal infiltration of mast cells affecting various tissues of the body. It is grouped into six different subtypes according to the World Health Organization classification. It is called indolent systemic mastocytosis (ISM) when there is no evidence of end organ dysfunction, while the presence of end organ dysfunction defines aggressive systemic mastocytosis (ASM). When SM coexists with a clonal hematological disorder, it is classified as systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD). Over 80% of SM-AHNMD cases involve disorders of the myeloid cell lines. To our knowledge, there are only 8 reported cases to date of SM associated with a plasma cell disorder. We report a patient with ISM who was found to have concomitant smoldering multiple myeloma. His disease later progressed to ASM. We discuss this rare association between SM and a plasma cell disorder, and potential common pathophysiologic mechanisms linking the two disorders will be reviewed. We also discuss prognostic factors in SM as well as the management options considered during the evolution of the patient's disease.
A case report of systemic mastocytosis associated with multiple hematologic non–mast cell lineage diseases
AbstractSystemic mastocytosis (SM) is a hematological malignancy characterized by extracutaneous infiltration by atypical mast cells. Together with indolent SM, aggressive SM, and mast cell leukemia, the World Health Organization (WHO) recognizes another major disease subgroup: SM with an associated hematological neoplasm, which is characterized by the presence of a concurrent neoplasm, more commonly, a chronic myelomonocytic leukemia. While KIT D816V is commonly regarded as the driver mutation, the clinical presentation of SM is extremely varied. Treatment of SM might not be simple, but now more specific therapies tailored toward prognostic subgroups of patients have been developed. Here, we report a detailed description of clinical management and biological features of a systemic mastocytocis case associated with multiple hematologic non-mast cell lineage diseases.
Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease
AbstractOpe n Pe e r Re v ie w on Qe ios Ope n Pe e r Re v ie w on Qe ios Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease INSERM Source INSERM.(1999).Orphanet: an online rare disease and orphan drug data base.Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease.ORPHA:98849 Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease is a form of systemic mastocytosis (SM) associated with malignancy (other than mast cell leukemia).
Clinical and Biological Diversity of Clonal Hematological Non-Mast Cell Lineage Neoplasms Associated with Mastocytosis.
AbstractAbstract Abstract 4976 Background Mastocytosis has many features in common with other myeloproliferative neoplsms (MPN) and is recognized by the 2008 World Health Organization (WHO) as a major subgroup of MPNs. In 20-30% of patients with systemic mastocytosis (SM), an associated clonal hematological non mast cell lineage disease (AHNMD) is also diagnosed, and such an occurrence is recognized by WHO classification system as SM-AHNMD. The latter (AHNMD) includes predominantly myeloid neoplasms, but also rarely non-myeloid hematologic neoplasms. SM-AHMD often creates a clinicopathologic diagnostic challenge due to diverse clinical presentation and sometimes subtle morphologic findings. We reviewed the clinicopathologic features, cytogenetic and molecular findings, and clinical course of eight patients with SM-AHNMD. Methods Approximately 30,000 bone marrow biopsy reports recorded in the institutional electronic database at Moffitt Cencer Center from January 1996 to July 2009 were reviewed. Thirty patients with SM- were identified. Diagnosis was confirmed by bone marrow (BM) histology; SM- and AHNMD-components were classified according to WHO criteria. Immunophenotypic analyses were performed on fresh samples using flow cytometry and on paraffin-embedded samples using immunohistochemistry. Molecular analyses for assessment of immunoglobulin heavy and light chain gene rearrangement and for detection of activating c-Kit D816V point mutation, as well as cytogenetic study by karyotyping and FISH analysis were performed on available skin punch biopsy and bone marrow aspirate samples. Clinical presentation, laboratory and imaging data, therapeutic regimen and clinical course were reviewed. Results SM was diagnosed in 30 bone marrow biopsies (0.1 %). SM-AHNMD was diagnosed in 8 patients (27% of SM) over a 13 year period. The AHNMD was MDS (3 cases: 1 refractory anemia, 2 cases of refractory anemia with ringed sideroblasts), MDS/MPN (2 cases, CMML), AML (1 case), marginal zone lymphoma (1 case) and plasma cell myeloma (1 case, IgD monoclonal). Patients ranged in age from 54 to 78 years (average 57), with a male to female ratio of 1:1. At presentation, all patients (8/8) had cytopenia; two patients (2/8) additionally had monocytosis. Cytogenetic abnormalities were identified in 3 cases (3/4) [t(8;21), t(3;5), isochromsme 14, deletion 5q, trisomy 4]. Activating c-Kit (D816V) point mutation was detected in 3 cases (3/4). In six patients (6/8), SM was diagnosed concurrently with the AHNMD and the aberrant mast cell proliferation was observed only after complete histopathologic examination. One patient (1/8) had long-standing indolent SM with cutaneous manifestation, and a second patient (1/8) suffered from recurrent “hives” for 12-15 years which was later diagnosed as cutaneous mastocytosis, prior to the development of an AHNMD. These two patients were treated with Gleevec and/or antihistamines. Upon diagnosis, all patients (8/8) were managed according to standard treatment protocols for their AHNMD. The patient with AML with t(8;21) received daunrubicin and cytarabine induction chemotherapy and intrathecal methotrexate. She achieved remission, followed by multiple relapses. Conclusions SM-AHNMD is uncommon. AHNMD is usually myeloid, but can also be a lymphoid/plasma cell neoplasm. In the majority of our cases, mastocytosis was not clinically suspected and the patient's clinical presentation was related to the associated non-mast cell lineage neoplasm. SM-AHNMD might pose a histopathologic challenge that potentially could be missed; for the most part it is a histological diagnosis based on a combination of morphologic features and ancillary studies. Patients are managed according to the current protocols for their AHNMD. Symptoms related to mastocytosis are treated with antihistamines, as needed. Of note, unlike most patients with AML with t(8;21), the patient in our case series fared poorly with standard chemotherapy. The prognostic relevance and therapeutic implications of detecting SM associated with another hematologic malignancy and warrants further studies and remains to be clarified. Disclosures No relevant conflicts of interest to declare.
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.
