The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert anti-neoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations. Likewise, givinostat killed primary cells, but not their normal hematopoietic counterparts, from patients carrying CRLF2 rearrangements. At low doses, givinostat downregulated the expression of genes belonging to the JAK/STAT pathway and inhibited STAT5 phosphorylation. In vivo, givinostat significantly reduced engraftment of human blasts in patient-derived xenograft models of CRLF2-positive BCP-ALL. Importantly, givinostat killed ruxolitinib-resistant cells and potentiated the effect of current chemotherapy. Thus, givinostat in combination with conventional chemotherapy may represent an effective therapeutic option for these difficult-to-treat subsets of ALL. Lastly, the selective killing of cancer cells by givinostat may allow the design of reduced intensity regimens in CRLF2-rearranged Down syndrome-associated BCP-ALL patients with an overall benefit in terms of both toxicity and related complications.
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.|Department of Pediatric Hematology and Oncology, Leukemia Research Section, Edmond and Lily Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
A M
AM
Savino
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
J
J
Sarno
Department of Women's and Children's Health, University of Padova, Padova, Italy.
L
L
Trentin
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
M
M
Vieri
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
G
0000-0001-7077-8422
G
Fazio
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
M
M
Bardini
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
C
C
Bugarin
Preclinical R&D Department, Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy.
G
G
Fossati
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.|Hematology and Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
K L
KL
Davis
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
G
G
Gaipa
Department of Pediatric Hematology and Oncology, Leukemia Research Section, Edmond and Lily Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
S
S
Izraeli
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
L H
LH
Meyer
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.|Hematology and Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
G P
GP
Nolan
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
A
A
Biondi
Department of Women's and Children's Health, University of Padova, Padova, Italy.
G
G
Te Kronnie
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
C
C
Palmi
Tettamanti Research Center, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy.
G
G
Cazzaniga
D000293:Adolescent; D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D018121:Receptors, Cytokine / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C498762:CRLF2 protein, human; D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; C575255:givinostat; C540383:ruxolitinib