Open AccessBcl‐xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms
Author(s) -
Petiti Jessica,
Lo Iacono Marco,
Rosso Valentina,
Andreani Giacomo,
Jovanovski Aleksandar,
Podestà Marina,
Lame Dorela,
Gobbi Marco De,
Fava Carmen,
Saglio Giuseppe,
Frassoni Francesco,
Cilloni Daniela
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15730
Subject(s) - ruxolitinib , bcl xl , myelofibrosis , essential thrombocythemia , polycythemia vera , myeloproliferative neoplasm , cancer research , cd34 , myeloproliferative disorders , medicine , regulator , oncology , apoptosis , gene , biology , stem cell , bone marrow , genetics , programmed cell death
Myeloproliferative neoplasms are divided into essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Although ruxolitinib was proven to be effective in reducing symptoms, patients rarely achieve complete molecular remission. Therefore, it is relevant to identify new therapeutic targets to improve the clinical outcome of patients. Bcl‐xL protein, the long isoform encoded by alternative splicing of the Bcl‐x gene, acts as an anti‐apoptotic regulator. Our study investigated the role of Bcl‐xL as a marker of severity of MPN and the possibility to target Bcl‐xL in patients. 129 MPN patients and 21 healthy patients were enrolled in the study. We analysed Bcl‐xL expression in leucocytes and in enriched CD34+ and CD235a+ cells. Furthermore, ABT‐737, a Bcl‐xL inhibitor, was tested in HEL cells and in leucocytes from MPN patients. Bcl‐xL was found progressively over‐expressed in cells from ET, PV and PMF patients, independently by JAK2 mutational status. Moreover, our data indicated that the combination of ABT‐737 and ruxolitinib resulted in a significantly higher apoptotic rate than the individual drug. Our study suggests that Bcl‐xL plays an important role in MPN independently from JAK2 V617F mutation. Furthermore, data demonstrate that targeting simultaneously JAK2 and Bcl‐xL might represent an interesting new approach.