2. Academic Validation
  3. A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients

A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients

  • Biomed Pharmacother. 2024 May:174:116537. doi: 10.1016/j.biopha.2024.116537.
Sara Rossi 1,  Vanessa Tatangelo 2,  Maria Dichiara 1,  Stefania Butini 1,  Sandra Gemma 1,  Simone Brogi 3,  Silvia Pasquini 4,  Martina Cappello 5,  Fabrizio Vincenzi 5,  Katia Varani 5,  Ludovica Lopresti 2,  Margherita Malchiodi 6,  Chiara Carrara 6,  Alessandro Gozzetti 6,  Monica Bocchia 6,  Giuseppe Marotta 7,  Laura Patrussi 8,  Gabriele Carullo 9,  Cosima T Baldari 2,  Giuseppe Campiani 10
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 2 Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 3 Department of Pharmacy, University of Pisa, Via Bonanno, Pisa 56126, Italy.
  • 4 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Borsari 46, Ferrara 44121, Italy.
  • 5 Department of Translational Medicine, University of Ferrara, Via Borsari 46, Ferrara 44121, Italy.
  • 6 Haematology Unit, Department of Medical Sciences, Surgery and Neuroscience, University of Siena, Policlinico "Santa Maria alle Scotte", Viale Bracci, Siena 53100, Italy.
  • 7 Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Policlinico "Santa Maria alle Scotte", Viale Bracci, Siena 53100, Italy.
  • 8 Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy. Electronic address: patrussi2@unisi.it.
  • 9 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy. Electronic address: gabriele.carullo@unisi.it.
  • 10 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-7346, Iran.
PMID: 38579402 DOI: 10.1016/j.biopha.2024.116537
Abstract

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing Apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL Apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell Apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked Apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.

Keywords

Chronic lymphocytic leukemia; HDAC inhibitors; HDAC1; STAT4; blood malignancies; chlopynostat; p66Shc.

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