骨髓增殖性肿瘤(MPN)是以造血干细胞(HSC)水平改变为特征的疾病,其中JAK2突变是经典MPN(真性红细胞增多症,原发性血小板增多症,和原发性骨髓纤维化)。我们和其他人先前证明二甲双胍降低JAK2V617F临床前MPN模型中外周血的脾肿大和血小板计数,这突出了双胍治疗MPN的抗肿瘤潜力。苯乙双胍是一种双胍,已用于治疗糖尿病,但由于其可能引起患者乳酸性酸中毒而被撤回。
我们在此旨在研究苯乙双胍在Jak2V617F敲入MPN小鼠中MPN疾病负荷和干细胞功能中的作用。
在SET2JAK2V67F细胞中,体外苯乙双胍处理降低细胞活力并增加细胞凋亡。在Jak2V617F敲入小鼠中使用40mg/kg苯乙双胍的长期治疗增加了LSK的频率,骨髓祖细胞(MP),和骨髓中的多能祖细胞(MPP)。苯乙双胍治疗不影响外周血计数,脾脏重量,巨核细胞计数,红细胞前体频率,或离体克隆能力。用苯乙双胍离体处理来自Jak2V617F敲入小鼠的骨髓细胞不影响受体小鼠的血液学参数或移植。
苯乙双胍增加了LSK的百分比,MP,和MPP人口,但并未降低Jak2V617F敲入小鼠的疾病负担。需要进一步研究苯乙双胍对早期造血祖细胞的影响。
Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2V617F pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment.
Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients.
We herein aimed to investigate the effects of
phenformin in MPN disease burden and stem cell function in Jak2V617F-knockin MPN mice.
In vitro
phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2V67F cells. Long-term treatment with 40 mg/kg
phenformin in Jak2V617F knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2V617F knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice.
Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2V617F-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.