Hind Bouzid

All Publications

• Anti-KIT antibody, briquilimab, induces mast cell apoptosis and depletion in nonhuman primates. The Journal of allergy and clinical immunology Lee, S. E., Bouzid, H., Kwan, C., Sharma, A., Romo, A. R., Huang, R., Zhan, I., Banfield, C., Parnes, J. R., Smider, V. V., Yu, M., Kwon, H. S., Pang, W. W. 2025; 156 (5): 1328-1340

  Abstract

  Mast cells (MCs) play a critical role in many allergic and inflammatory reactions in healthy and disease states. Current therapeutic strategies to treat MC-mediated diseases aim to suppress MC activation by using small molecule inhibitors or antibodies targeting specific signaling receptors on MCs. However, these strategies require long-term drug exposure, which has inherent limitations including increased patient burden and potential toxicity. Moreover, the redundancy between multiple signaling pathways concomitantly regulating MC activation can lead to insufficient MC suppression.We sought to develop a novel therapeutic strategy using briquilimab, an aglycosylated anti-KIT mAb, to deplete MCs via KIT signaling inhibition.Inhibition of KIT by briquilimab was evaluated in vitro in KIT-expressing cell lines and primary human MCs. Briquilimab safety, pharmacokinetics, and MC depletion were evaluated in nonhuman primates (NHPs).Briquilimab potently blocked stem cell factor (SCF) ligand binding to KIT and inhibited SCF/KIT signaling and primary MC degranulation and survival, leading to MC apoptosis via the PI3K/AKT pathway in vitro. Additionally, aglycosylation of briquilimab mitigated unwanted MC activation. In NHPs, single- and multi-dose high, long-term exposure to briquilimab was well tolerated with mild to moderate, but reversible adverse effects and successfully depleted various tissue MCs, including lung, skin, and colon, in a dose-dependent manner.Briquilimab effectively inhibits SCF/KIT signaling and induces MC apoptosis, leading to profound and durable MC depletion in NHPs, and may provide a safe and novel therapeutic option to treat MC-mediated diseases.

  View details for DOI 10.1016/j.jaci.2025.07.019

  View details for PubMedID 40754230

• TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice. Cell stem cell Matatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., Vlasschaert, C., Buttigieg, M. M., Fan, C. W., Carcamo, S., Cao, R., Kennedy, D. E., Maknojia, A. A., Thatavarty, A., Fernandez Sanchez, J. V., Bouzid, H., Veeraragavan, S., Crocker, S., Goodell, M. A., Rodriguez, A., Jaiswal, S., Rauh, M. J., Papapetrou, E. P., Marro, S. G., King, K. Y. 2025

  Abstract

  Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

  View details for DOI 10.1016/j.stem.2025.06.006

  View details for PubMedID 40609533

• Clonal hematopoiesis is associated with protection from Alzheimer's disease. Nature medicine Bouzid, H., Belk, J. A., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M. R., Ahmad, H., Nachun, D., Yao, W., Beiser, A., Bick, A. G., Bis, J. C., Fornage, M., Longstreth, W. T., Lopez, O. L., Natarajan, P., Psaty, B. M., Satizabal, C. L., Weinstock, J., Larson, E. B., Crane, P. K., Keene, C. D., Seshadri, S., Satpathy, A. T., Montine, T. J., Jaiswal, S. 2023

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10-5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

  View details for DOI 10.1038/s41591-023-02397-2

  View details for PubMedID 37322115

  View details for PubMedCentralID 4306669

• Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. Nature Weinstock, J. S., Gopakumar, J., Burugula, B. B., Uddin, M. M., Jahn, N., Belk, J. A., Bouzid, H., Daniel, B., Miao, Z., Ly, N., Mack, T. M., Luna, S. E., Prothro, K. P., Mitchell, S. R., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Sinner, M. F., von Falkenhausen, A. S., Kääb, S., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Hou, L., Lloyd-Jones, D. M., Redline, S., Cade, B. E., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Qiao, D., Palmer, N. D., Freedman, B. I., Bowden, D. W., Cho, M. H., DeMeo, D. L., Vasan, R. S., Yanek, L. R., Becker, L. C., Kardia, S. L., Peyser, P. A., He, J., Rienstra, M., Van der Harst, P., Kaplan, R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Arnett, D. K., Irvin, M. R., Tiwari, H., Cutler, M. J., Knight, S., Muhlestein, J. B., Correa, A., Raffield, L. M., Gao, Y., de Andrade, M., Rotter, J. I., Rich, S. S., Tracy, R. P., Konkle, B. A., Johnsen, J. M., Wheeler, M. M., Smith, J. G., Melander, O., Nilsson, P. M., Custer, B. S., Duggirala, R., Curran, J. E., Blangero, J., McGarvey, S., Williams, L. K., Xiao, S., Yang, M., Gu, C. C., Chen, Y. I., Lee, W. J., Marcus, G. M., Kane, J. P., Pullinger, C. R., Shoemaker, M. B., Darbar, D., Roden, D. M., Albert, C., Kooperberg, C., Zhou, Y., Manson, J. E., Desai, P., Johnson, A. D., Mathias, R. A., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Satpathy, A. T., Natarajan, P., Kitzman, J. O., Whitsel, E. A., Reiner, A. P., Bick, A. G., Jaiswal, S. 2023

  Abstract

  Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

  View details for DOI 10.1038/s41586-023-05806-1

  View details for PubMedID 37046083

  View details for PubMedCentralID 4624443

• Acquired TET2 mutation in one patient with familial platelet disorder with predisposition to AML led to the development of pre-leukaemic clone resulting in T2-ALL and AML-M0. Journal of cellular and molecular medicine Manchev, V. T., Bouzid, H., Antony-Debré, I., Leite, B., Meurice, G., Droin, N., Prebet, T., Costello, R. T., Vainchenker, W., Plo, I., Diop, M., Macintyre, E., Asnafi, V., Favier, R., Baccini, V., Raslova, H. 2017; 21 (6): 1237-1242

  Abstract

  Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1R174Q mutation who developed at the age of 42 years a T2-ALL and, 2 years after remission, an AML-M0. Both AML-M0 and T2-ALL blast populations demonstrated a loss of 1p36.32-23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRγ and TCRδ and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood-derived CD34+ cells 5 years prior to T2-ALL development revealed only the missense TET2P1962T mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2-ALL and AML-M0 clones. This result suggests that TET2P1962T mutation in association with germline RUNX1R174Q mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations.

  View details for DOI 10.1111/jcmm.13051

  View details for PubMedID 27997762

  View details for PubMedCentralID PMC5431233