B-cell chronic lymphocytic leukemia (B-CLL IntroductionThe tumor suppressor TP53 plays an important role in the control of key genes involved in the regulation of DNA repair, cell cycle, and apoptosis. 1,2 p53 is activated in response to DNA damage or other forms of stress, protecting cells from malignant transformation. This is the reason why p53 is frequently inactivated in human cancer. p53 is a short-lived protein, and its cellular level is controlled by the rate at which it is degraded. Although several U3 ubiquitin ligases have been implicated in p53 ubiquitylation and degradation, MDM2 appears to function as a master regulator of p53. 3,4 MDM2 not only facilitates p53 degradation, but it also binds p53 and inhibits its transcriptional activity. Therefore, inhibitors of p53-MDM2 binding are expected to stabilize and activate p53. Recently, the first potent and selective small-molecule antagonists of MDM2, the nutlins, have been shown to activate the p53 pathway in cancer cells with wild-type p53 in vitro and in vivo. 5 B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5 ϩ B lymphocytes. 6 TP53 is mutated in only 5% to 10% of B-CLL cases at diagnosis, but in nearly 30% in chemotherapy-resistant tumors. TP53 mutation is associated with poor clinical outcome, shorter survival, and lack of response to therapy with purine nucleoside analogs or alkylating agents. [7][8][9][10][11] In fact, alterations in the TP53 gene are among the worst prognostic indicators for B-CLL. [12][13][14] Most of the chemotherapeutic drugs currently used induce cell cycle arrest or apoptosis through activation of p53, and p53 inactivation leads to chemoresistance. 1,2 Chemotherapeutic drugs, including purine analogs, topoisomerase inhibitors, and alkylating agents, have been shown to effectively increase p53 levels in B-CLL. 15,16 Thus, p53 activation is considered among the critical molecular events in chemotherapy-induced apoptosis in B-CLL cells. Although TP53 is mutated in only 5% to 10% of patients, the p53 pathway could be altered at a higher frequency, thus effectively attenuating p53 function. One of the mechanisms involved in p53 stabilization in response to DNA damage is its phosphorylation by ataxia telangiectasia mutated (ATM) protein. 1,2 Interestingly, ATM is inactivated in 10% to 20% of B-CLL cases, thus providing an alternative way to disable p53 function. [17][18][19][20] Tumors with alterations upstream of p53 would not respond adequately to genotoxic chemotherapeutics that act through the p53 pathway (eg, alkylating agents such as chlorambucil and cyclophosphamide; purine nucleosides such as fludarabine and cladribine; or topoisomerase inhibitors such as doxorubicin and mitoxantrone). Therefore, new therapies that overcome these For personal use only. on May 11, 2018. by guest www.bloodjournal.org From defects by acting directly on p53 stability may benefit these patients. Nutlins activate p53 by releasing it from MDM2-mediated negative control and thus compensate for d...

Gamete failure-derived infertility affects millions of people worldwide; for many patients, gamete donation by unrelated donors is the only available treatment. Embryonic stem cells (ESCs) can differentiate in vitro into germ-like cells, but they are genetically unrelated to the patient. Using an in vitro protocol that aims at recapitulating development, we have achieved, for the first time, complete differentiation of human induced pluripotent stem cells (hiPSCs) to postmeiotic cells. Unlike previous reports using human ESCs, postmeiotic cells arose without the over-expression of germline related transcription factors. Moreover, we consistently obtained haploid cells from hiPSCs of different origin (keratinocytes and cord blood), produced with a different number of transcription factors, and of both genetic sexes, suggesting the independence of our approach from the epigenetic memory of the reprogrammed somatic cells. Our work brings us closer to the production of personalized human gametes in vitro.