Publications

 

Katja Gabriele Weinacht, MD, PhD

Publications

  • Hematopoietic Cell Transplantation for Wiskott-Aldrich syndrome: A PIDTC Report. Blood advances Alexander, J. L., Dávila Saldaña, B. J., Brazauskas, R., Dammalapati, S. G., Griffith, L. M., Shah, A. J., Shimano, K. A., Ochs, H. D., Bleesing, J., Ebens, C. L., Kapadia, M., Bauchat, A., Kapoor, N., Oved, J. H., Eissa, H., Lust, H., Keller, M. D., Haines, H., Chandrakasan, S., Talano, J. M., Rayes, A., Madden, L. M., Shereck, E. B., Miller, H. K., Forbes Satter, L. R., Martinez, C. A., Rozmus, J., Bednarski, J. J., Yu, L. C., Chellapandian, D., Aquino, V. M., Knutsen, A. P., Chong, H., Chopek, A., Gillio, A. P., Joshi, A., Rangarajan, H. G., Moore, T. B., Andolina, J. R., DeSantes, K., Vander Lugt, M. T., Prockop, S. E., Shyr, D., Sullivan, K. E., Parikh, S. H., Weinacht, K. G., Torgerson, T. R., Marsh, R. A., Dvorak, C. C., Chan, A. Y., Haddad, E., Heimall, J., Pulsipher, M. A., Leiding, J. W., Kohn, D. B., Puck, J. M., Notarangelo, L. D., Rawlings, D. J., Cowan, M. J., Petrovic, A., Pai, S. Y., Burroughs, L. M. 2025

    Abstract

    Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to impact overall survival (OS). The influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium (PIDTC) from 1990-2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced intensity regimens were associated with lower T cell and myeloid donor chimerism, particularly when non-busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hotspot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS following HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This study was registered at www.clinicaltrials.gov as #NCT02064933.

    View details for DOI 10.1182/bloodadvances.2025017662

    View details for PubMedID 41346295

  • Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development. Science immunology Mohammed, A., Wang, W., Arreola, M., Solomon, B. D., Slepicka, P. F., Hubka, K. M., Nguyen, H. D., Zheng, Z., Chavez, M. G., Yeh, C. Y., Kim, D. K., Ma, M. R., Martin, E., Li, L., Pasca, A. M., Winn, V. D., Gifford, C. A., Kedlian, V. R., Park, J. E., Khatri, P., Hollander, G. A., Roncarolo, M. G., Sebastiano, V., Teichmann, S. A., Gentles, A. J., Weinacht, K. G. 2025; 10 (107): eado4720

    Abstract

    Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut-derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut-derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.

    View details for DOI 10.1126/sciimmunol.ado4720

    View details for PubMedID 40315299

  • Reticular Dysgenesis-Associated Adenylate Kinase 2 Deficiency Has Opposing Metabolic Consequences on Granulopoiesis and Lymphopoiesis Wang, W., Arreola, M., Mohammed, A., Weinacht, K. G. ELSEVIER. 2024: 1276

    View details for DOI 10.1182/blood-2024-210954

    View details for Web of Science ID 001415685200023

  • 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

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