Publications

 

Katja Gabriele Weinacht, MD, PhD

Publications

  • Failure of metabolic checkpoint control during late-stage granulopoiesis drives neutropenia in reticular dysgenesis. Blood Wang, W., Arreola, M., Mathews, T., DeVilbiss, A. W., Zhao, Z., Martin-Sandoval, M., Mohammed, A., Benegiamo, G., Awani, A., Goeminne, L. J., Dever, D. P., Nakauchi, Y., Porteus, M. H., Pavel-Dinu, M., Al Herz, W., Auwerx, J., Morrison, S. J., Weinacht, K. G. 2024

    Abstract

    Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Here, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in reticular dysgenesis patient samples with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (mTOR) signaling and anabolic pathway activation. This conserved nutrient homeostasis and maintained cell survival and proliferation. In contrast, during late-stage granulopoiesis, metabolic checkpoints were ineffective, leading to a paradoxical upregulation of mTOR activity and energy-consuming anabolic pathways such as ribonucleoprotein synthesis in AK2-deficient cells. This caused nucleotide imbalance, including highly elevated AMP and IMP levels, the depletion of essential substrates such as NAD+ and aspartate, and ultimately resulted in proliferation arrest and demise of the granulocyte lineage. Our findings suggest that even severe metabolic defects can be tolerated with the help of metabolic checkpoints but that the failure of such checkpoints in differentiated cells results in a catastrophic loss of homeostasis.

    View details for DOI 10.1182/blood.2024024123

    View details for PubMedID 39378586

  • Transcriptional and epigenetic characterization of a new in vitro platform to model the formation of human pharyngeal endoderm. Genome biology Cipriano, A., Colantoni, A., Calicchio, A., Fiorentino, J., Gomes, D., Moqri, M., Parker, A., Rasouli, S., Caldwell, M., Briganti, F., Roncarolo, M. G., Baldini, A., Weinacht, K. G., Tartaglia, G. G., Sebastiano, V. 2024; 25 (1): 211

    Abstract

    The Pharyngeal Endoderm (PE) is an extremely relevant developmental tissue, serving as the progenitor for the esophagus, parathyroids, thyroids, lungs, and thymus. While several studies have highlighted the importance of PE cells, a detailed transcriptional and epigenetic characterization of this important developmental stage is still missing, especially in humans, due to technical and ethical constraints pertaining to its early formation.Here we fill this knowledge gap by developing an in vitro protocol for the derivation of PE-like cells from human Embryonic Stem Cells (hESCs) and by providing an integrated multi-omics characterization. Our PE-like cells robustly express PE markers and are transcriptionally homogenous and similar to in vivo mouse PE cells. In addition, we define their epigenetic landscape and dynamic changes in response to Retinoic Acid by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of multiple high-throughput datasets leads to the identification of new putative regulatory regions and to the inference of a Retinoic Acid-centered transcription factor network orchestrating the development of PE-like cells.By combining hESCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and the modeling of their developmental defects in genetic syndromes.

    View details for DOI 10.1186/s13059-024-03354-z

    View details for PubMedID 39118163

    View details for PubMedCentralID 5241818

  • Human Immune repertoire and gene expression in pediatric and adult SARS-CoV2 infected patients using single cell multi-omics approaches Ji, X., Yonker, L., Miranda, M., Kinane, T., Chang, M., Suresh, S., Kiany, S., Weinacht, K., Maecker, H. AMER ASSOC IMMUNOLOGISTS. 2024

    View details for DOI 10.4049/jimmunol.212.supp.0236.4847

    View details for Web of Science ID 001368900700012

  • A multidisciplinary approach to unraveling genetic forms of immune dysregulation in children with refractory multilineage cytopenia Gernez, Y., Sathi, B., Camacho, J., Rao, L., Glader, B., Singh, D., Hoyte, E., Lewis, D., Roncarolo, M., Chien, M., Bacchetta, R., Weinacht, K. MOSBY-ELSEVIER. 2024: AB186

    View details for Web of Science ID 001267526000574

  • The rise of haplo: a quest for the perfect graft. Blood Weinacht, K. G. 2024; 143 (3): 193-195

    View details for DOI 10.1182/blood.2023022428

    View details for PubMedID 38236615

  • Accelerating Immune Reconstitution in HSCT Patients through iPSC-Derived Thymic Epithelial Cells Mohammed, A., Hanh Dan Nguyen, Hubka, K., Wang, W., Slepicka, P., Solomon, B., Arreola, M., Zheng, Z., Gentles, A., Weinacht, K. G. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-186901

    View details for Web of Science ID 001159306701217

  • Loss of Metabolic Control Beyond the Promyelocyte Stage Resolves Myeloid Maturation Arrest in Reticular Dysgenesis Wang, W., Arreola, M., Mathews, T., Devilbiss, A., Zhao, Z., Morrison, S., Weinacht, K. G. AMER SOC HEMATOLOGY. 2023

    View details for DOI 10.1182/blood-2023-185497

    View details for Web of Science ID 001159900802188

  • Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients. Journal of clinical medicine Levitte, S., Ganguly, A., Frolik, S., Guevara-Tique, A. A., Patel, S., Tadas, A., Klein, O., Shyr, D., Agarwal-Hashmi, R., Beach, L., Callard, E., Weinacht, K., Bertaina, A., Thakor, A. S. 2023; 12 (13)

    Abstract

    Graft versus host disease (GVHD) is one of the most serious complications following stem cell transplant in children and is a major cause of morbidity and mortality. Corticosteroids remain the mainstay of treatment, and although a majority of children respond to systemic steroids, those refractory to or dependent upon corticosteroids suffer from complications secondary to long-term steroid administration. This problem has prompted consideration of steroid-sparing treatment strategies, although the time to clinical remission can be variable. Intraarterial corticosteroid delivery has been used in adults as a rescue therapy in steroid-resistant patients, but its use in children has been limited. We investigated the feasibility of intraarterial steroid administration into the bowel and/or liver in a cohort of six pediatric patients with acute GVHD. All patients successfully underwent treatment with no serious adverse effects. Five of five (100%) patients with gastrointestinal bleeding due to GVHD had rapid symptom improvement by 48 h, which was durable up to three weeks. Three of four (75%) patients with hepatic GVHD had improved cholestasis following intraarterial steroid administration. Our experience with this small cohort preliminarily demonstrated the feasibility and safety of intraarterial steroid administration in children with acute GVHD. This approach warrants consideration as a rescue therapy in steroid-refractory cases and as a "bridge" therapy for children with severe acute GVHD who are transitioning to steroid-sparing regimens.

    View details for DOI 10.3390/jcm12134229

    View details for PubMedID 37445274

  • Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition. Frontiers in immunology Gernez, Y., Narula, M., Cepika, A., Valdes Camacho, J., Hoyte, E. G., Mouradian, K., Glader, B., Singh, D., Sathi, B., Rao, L., Tolin, A. L., Weinberg, K. I., Lewis, D. B., Bacchetta, R., Weinacht, K. G. 2023; 14: 1328005

    Abstract

    Biallelic mutations in the ACP5 gene cause spondyloenchondrodysplasia with immune dysregulation (SPENCDI). SPENCDI is characterized by the phenotypic triad of skeletal dysplasia, innate and adaptive immune dysfunction, and variable neurologic findings ranging from asymptomatic brain calcifications to severe developmental delay with spasticity. Immune dysregulation in SPENCDI is often refractory to standard immunosuppressive treatments. Here, we present the cases of two patients with SPENCDI and recalcitrant autoimmune cytopenias who demonstrated a favorable clinical response to targeted JAK inhibition over a period of more than 3 years. One of the patients exhibited steadily rising IgG levels and a bone marrow biopsy revealed smoldering multiple myeloma. A review of the literature uncovered that approximately half of the SPENCDI patients reported to date exhibited increased IgG levels. Screening for multiple myeloma in SPENCDI patients with rising IgG levels should therefore be considered.

    View details for DOI 10.3389/fimmu.2023.1328005

    View details for PubMedID 38347954

  • Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients Journal of Clinical Medicine Levitte, s., Ganguly, A., Frolik, S., Guevara-Tique, A., et al 2023; 12 (4229)

    View details for DOI 10.3390/jcm12134229

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