HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms

Abstract

Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.

Histone Deacetylase 11 Knockdown Blocks Larval Development and Metamorphosis in the Red Flour Beetle, Tribolium castaneum

“…HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs (Thole et al, 2017). Inhibitor studies in mouse models showed that HDAC11 plays an important role in oncogene-induced hematopoiesis in myeloproliferative neoplasms (MPNs) (Yue et al, 2020). Based on these previous findings, it is tempting to hypothesize that HDAC11 knockdown may induce the death of some internal tissues resulting in the dark color detected in larvae.…”

“…HDAC11 first described in 2002 is a unique member class IV HDAC family since it is not homologous with RPD3 or HDA1 yeast enzymes (Gao et al, 2002). Selective/class-specific inhibitors targeting HDAC11 have been developed for treating patients with myeloproliferative neoplasms (MPN) (Yue et al, 2020). HDAC11 shows some sequence similarity to class I and II HDACs and is highly conserved in invertebrates and plants (Yang and Seto, 2008).…”

Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms

“…We, along with our collaborators, demonstrated a role for HDAC11 in HSPCs in a transplantation mouse model of MPN driven by MPL-W515L. Data obtained using HDAC11 -null mice and MPN patient samples treated with selective HDAC11 inhibitors suggest that HDAC11 contributes to the neoplastic nature of MPN cells but not normal hematopoiesis ( 50 ). Subsequent studies using global acetylomic profiling following HDAC11 inhibition identified glycolytic enzymes (e.g., enolase-1 (ENO-1)) as potential substrates of HDAC11.…”

“…Finally, we have recently shown a role for HDAC11 in MPN, but not normal, hematopoiesis, in one of the first reports that shows isoform selective HDAC targeting specifically impedes malignant hematopoiesis without affecting the steady state and transplantation reconstitution of normal bone marrow cells. This suggests HDAC11 may be a therapeutic target to antagonize MPN with minimal adverse effect on normal hematopoiesis ( 50 ).…”

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

“…Notably, cells with mutationally active JAK2 were more sensitive to HDAC inhibition, which also displayed efficacy in murine models of MPN as a monotherapy and elicited augmented therapeutic responses in combination with ruxolitinib [ 93 , 95 , 98 ]. A recent study demonstrated that genetic deletion of HDAC11 expression impeded disease in a murine MPN model but did not affect normal hematopoiesis [ 99 ]. The development of more selective HDAC inhibitors will likely play an important role in determining the extent to which targeting this class of proteins can provide therapeutic efficacy with limited adverse effects.…”