Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases

Abstract

Histone deacetylase inhibitors (HDACi) had emerged as promising drugs in leukaemia, but their toxicity due to lack of specificity limited their use. Therefore, there is a need to elucidate the role of HDACs in specific settings. The study of HDAC expression in childhood leukaemia could help to choose more specific HDACi for selected candidates in a personalized approach. We analysed HDAC1-11, SIRT1, SIRT7, MEF2C and MEF2D mRNA expression in 211 paediatric patients diagnosed with acute leukaemia. There was a global overexpression of HDACs, while specific HDACs correlated with clinical and biological features, and some even predicted outcome. Thus, some HDAC and MEF2C profiles probably reflected the lineage and the maturation of the blasts and some profiles identified specific oncogenic pathways active in the leukaemic cells. Specifically, we identified a distinctive signature for patients with KMT2A (MLL) rearrangement, with high HDAC9 and MEF2D expression, regardless of age, KMT2A partner and lineage. Moreover, we observed an adverse prognostic value of HDAC9 overexpression, regardless of KMT2A rearrangement. Our results provide useful knowledge on the complex picture of HDAC expression in childhood leukaemia and support the directed use of specific HDACi to selected paediatric patients with acute leukaemia.

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

“…Overexpression of HDACs such as HDAC9 and SIRT1 have an adverse prognosis in MLL-rearranged lymphoblastic leukemia [ 499 ], noteworthy, the latter alters the acetylation of critical genes including TP53, MYC, and NF-kβ, causing drug resistance [ 28 , 499 – 503 ]. Indeed, a vast spectrum of HDAC inhibitors (iHDACs) are in development, and some have obtained FDA approval [ 504 ].…”

“…Histone deacetylase family members play an essential role in regulating the MYC level [ 738 ]. For instance, SIRT1 is a class III histone deacetylase responsible for the acetylation of critical genes, including TP53, MYC, and NF-kβ [ 28 , 499 – 503 ]. On the other hand, HDAC7 that is mostly decreased in various types of leukemia can downregulate MYC[ 505 ].…”

Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

“…Notably, HDAC9 expression levels above the median value were associated with a reduced five-year event-free survival, especially in B-lineage CD10-positive ALL patients. The relationship between a poor prognosis and high levels of HDAC9 expression in B-cell precursor ALL patients was confirmed by Vega-García et al [112], who analyzed mRNA expression levels in cells from pediatric patients diagnosed with acute leukemia.…”

“…AML is an aggressive cancer that mostly arises in stem cells in the bone marrow of affected adults. High levels of HDAC9 expression in AML, as with other cancers, are significantly correlated with a diminished overall survival [112]. Bradbury et al [113] explored HDAC9 expression in primary AML blasts and compared their results to HDAC9 levels in four other cell types, including quiescent or cycling CD34 + progenitor cells from umbilical cord blood and cycling CD34 + progenitors taken from peripheral mononuclear cells that were harvested from granulocyte colony-stimulating factor (GCSF)-stimulated adult donors.…”

MYC’s Fine Line Between B Cell Development and Malignancy

“…For instance, HDAC9 is associated with an adverse prognosis, whereas SIRT1 is involved in drug resistance through its regulation of the acetylation of the TP53, MYC, and NF-κβ genes. Consequently, HDAC inhibitors (HDACis) have emerged as potential therapeutic options in treating hematological malignancies [94,95]. However, conceptualizing the role of HDACs in leukemia as inducers of malignant transformation would be a too simplistic view, given that some histone deacetylases, such as HDAC7, carry out an opposite function.…”