DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pancytopenia due to IKZF1 mutations — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePancytopenia due to IKZF1 mutations maps to a 1-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
No approved-drug candidate for pancytopenia due to ikzf1 mutations 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
IKAROS family zinc finger 1 (IKZF1) — IKZF1 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 3-chloro-4-methylphenyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9Q2D · 2.94 Å · ligand 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea (85C). Experimental structure, not a prediction.
What the evidence adds up to
A 2020 case report describes a three-month-old male infant with common variable immunodeficiency, autoimmune haemolytic anaemia, and pancytopenia due to a heterozygous missense variant in IKZF1 (c.427C>T; p.R143W). The mutant protein showed a partial dominant-negative effect on pericentromeric targeting and DNA binding in cotransfection studies. The infant underwent haematopoietic stem cell transplantation. No drug treatment for the pancytopenia itself is reported in this abstract.
A 2022 case report of a single family carrying a novel IKZF1 mutation found that the same genetic defect produced asymptomatic selective IgA deficiency in the father and chronic immune thrombocytopenia in the younger brother, while the proband had common variable immunodeficiency. This demonstrates highly variable clinical penetrance even within the same family and environment. The authors recommend genetic testing as part of routine immunological workup but do not report any drug therapy for pancytopenia.
A 2020 study of 164 adult B-cell acute lymphoblastic leukaemia patients found that IKZF1 mutation was an adverse prognostic factor. Among patients with the mutation, the three-year overall survival was 55.3% ± 7.5% and leukaemia-free survival was 48.3% ± 7.6% in those who received allogeneic haematopoietic stem cell transplantation, compared with 32.9% ± 11.8% and 28.4% ± 10.3% in those who received chemotherapy alone. These differences were statistically significant. No drug is mentioned as a treatment for pancytopenia in this context.
What is still missing: no clinical trial has tested any drug specifically for pancytopenia caused by IKZF1 mutations. The only intervention with reported survival benefit is allogeneic stem cell transplantation, which is not a drug. No data exist on whether any existing immunomodulatory or haematopoietic agent can improve blood counts in these patients. Patient stratification by mutation type and penetrance remains unexplored in treatment studies. Funding for preclinical drug screening or a dedicated trial is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Pediatric Hematology/Oncology · 2020 · 11 citations · open access
Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS
AbstractOBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. MATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.
Frontiers in Immunology · 2022 · 8 citations · open access
Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family
AbstractHere we describe a novel mutation in the IKZF gene encoding IKAROS, as the cause of common variable immunodeficiency (CVID). The identification of the same defect in the IKZF gene with manifestations of asymptomatic selective IgA deficiency and chronic ITP in the father and her younger brother, respectively, demonstrates the large variability of this genetic defect in one single family, while living in the same environment with a relatively similar genetic background. As discussed, clinical penetrance of the molecular defects identified by mutations in IKZF and other common gene defects in CVID in familial immune-related abnormalities makes genetic testing a necessary step for diagnosis, management, and counseling, as part of the routine immunological workup.
[Ikaros Family Zinc Finger 1 Mutation Is an Adverse Prognostic Factor for Patients with Adult B-Cell Acute Lymphoblastic Leukemia].
AbstractOBJECTIVE: To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) accompanied with Ikaros family zinc finger 1 (IKZF1) mutation, and to explore the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome of patients. METHODS: The clinical data of 164 adult B-ALL patients who received IKZF-1 mutation detection by capillary electrophoresis of bone marrow were collected, and the relationship between the IKZF-1 gene mutation and the prognosis of adult B-ALL patients was analyzed. RESULTS: mutation, the 3-year OS and LFS rates were significantly higher in the transplantation group (55.3%±7.5%, 48.3%±7.6%) than those in the chemotherapy group (32.9%±11.8%, 28.4%±10.3%) with IKZF1 mutation (P＜0.05). CONCLUSION: IKZF1 mutation is an adverse prognostic factor for adult B-ALL patients, However, allo-HSCT significantly improves the OS and LFS of patients and also their clinical outcomes.
Image_1_Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family.jpeg
Abstract<p>Here we describe a novel mutation in the IKZF gene encoding IKAROS, as the cause of common variable immunodeficiency (CVID). The identification of the same defect in the IKZF gene with manifestations of asymptomatic selective IgA deficiency and chronic ITP in the father and her younger brother, respectively, demonstrates the large variability of this genetic defect in one single family, while living in the same environment with a relatively similar genetic background. As discussed, clinical penetrance of the molecular defects identified by mutations in IKZF and other common gene defects in CVID in familial immune-related abnormalities makes genetic testing a necessary step for diagnosis, management, and counseling, as part of the routine immunological workup.</p>
Assessment of chromatin remodeling of acute myeloid leukemia cells treated with gilteritinib: a case report
AbstractAbstract Background Acute myeloid leukemia is a hematological malignancy characterized by acquired genomic aberrations. Mutations in the FMS-like tyrosine kinase 3 gene cause constitutive activation of downstream signaling pathways, thereby driving disease progression and conferring a poor prognosis. Gilteritinib, a tyrosine kinase inhibitor, is a promising treatment for FMS-like tyrosine kinase 3-mutated acute myeloid leukemia. However, gilteritinib resistance remains a significant concern, and its underlying mechanisms are not yet understood. Case presentation A 65-year-old Japanese male patient who was receiving regular hemodialysis developed pancytopenia in 2017. He required recurrent red blood cell transfusions due to anemia in 2018. In 2019, he was diagnosed with myelodysplastic syndrome with excess blasts. We administered three courses of azacitidine but ceased it due to severe cytopenia. His disease had transformed to acute myeloid leukemia. The fourth course of azacitidine was administered, but it was ineffective. Since a tyrosine kinase domain mutation in FMS-like tyrosine kinase 3 was detected in the acute myeloid leukemia cells, we administered gilteritinib at a dose of 120 mg. Although the treatment initially showed efficacy, the disease progressed, and he died 7 days after the initiation of gilteritinib. To assess the epigenetic changes in acute myeloid leukemia during the treatment with gilteritinb, we performed the assay for transposase-accessible chromatin with sequencing using the leukemia cells obtained from the patient before and after gilteritinib treatment. After the treatment, greater than fivefold changed assay for transposase-accessible chromatin peaks were detected in 137 (upregulated) and 105 (downregulated) regions. Among them, half of the regions were located in the intergenic regions. A Gene Ontology analysis of affected genes listed the mitogen‑activated protein kinase pathway, which is potentiated by the FMS-like tyrosine kinase 3 genetic mutations in leukemia cells. No significant changes were noted at the FMS-like tyrosine kinase 3 locus. On the gene locus of PPP2R2B, a known cancer-associated gene, the peaks were decreased, suggesting reduced chromatin accessibility. Conversely, upregulation peaks were observed on the gene locus and adjacent noncoding region of PDGFD that is associated with the progression of various types of cancer including acute myeloid leukemia. Conclusions Our study demonstrated the epigenetic changes in acute myeloid leukemia cells that may be associated with gilteritinib resistance.
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.
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