Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia.
Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (>or=50 microg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.
Cimino
Giuseppe
G
Department of Cellular Biotechnology and Hematology, University of Rome La Sapienza, Rome, Italy.
Lo-Coco
Francesco
F
Fenu
Susanna
S
Travaglini
Lorena
L
Finolezzi
Erica
E
Mancini
Marco
M
Nanni
Mauro
M
Careddu
Angela
A
Fazi
Francesco
F
Padula
Fabrizio
F
Fiorini
Roberto
R
Spiriti
Maria Antonietta Aloe
MA
Petti
Maria Concetta
MC
Venditti
Adriano
A
Amadori
Sergio
S
Mandelli
Franco
F
Pelicci
Pier Giuseppe
PG
Nervi
Clara
C
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014212:Tretinoin; D014635:Valproic Acid