Remarkably, in the last decade, many other types of cancers were shown to be ROR1 positive (Zhang et al., 2012) and to overexpress is still under investigation. ROR1, would show an excellent response to a combination therapy with venetoclax and monoclonal antibodies against ROR1, since both drugs target the same malignant cells that have lost is a master regulator of cell survival (Croce and Reed, 2016) and Venetoclax was developed to kill malignant cells driven by the overexpression this protein (Pekarsky et al., 2018; Pekarsky and Croce, 2019). The development of Cirmtuzumab, was based on the discovery that the tyrosine kinase-like orphan receptor 1 (ROR1), a receptor of Wnt-5a, is frequently expressed on the surface of CLL cells but not in normal somatic tissues (Cui et al., 2016). Since Wnt5a-ROR1 binding on CLL cell surface initiates the non-canonical Wnt-5a pathway that promotes cell proliferation, Cirmtuzumab was developed as a humanized monoclonal antibody to compete with Wnt5a in the binding of ROR1, thus preventing the initiation of the proliferation signal (Pekarsky and Croce, 2019; Yu et al., 2017; Zhou et al., 2017). 2.?and Venetoclax In 1984 we investigated the t(14;18) chromosomal translocations, the hallmark of follicular lymphoma. Cimetropium Bromide These studies led to the discovery and characterization of the B-cell lymphoma 2 gene (gene from chromosome 18 next to the immunoglobulin heavy chain locus on chromosome 14, prompting to an excessive transcription and expression of (Tsujimoto et al., 1985; Tsujimoto et al., 1984). The mechanism of action of this oncogene, however, remained unknown until 1988 when a functional study revealed that, in IL-3-dependent haematopoietic progenitor, Cimetropium Bromide exogenous expression of Bcl-2 increased cell survival when the essential grow factor was removed. In this experiment, both overexpressing cells and control cells went into cycle arrest when IL-3 was removed. However, while control cells died within 72 hours, cells overexpressing did not (Vaux et al., 1988). These evidences indicated that overexpression supports cancer cell survival by preventing cell death rather than enhancing proliferation. This effect was noted in human cancers as well. For instance, in small low grade breast cancer with positive estrogen receptor/progesterone receptor (ER/PR) status and negative human epidermal growth factor receptor 2 (HER2) status, high expression of correlates with favorable prognostics (Dawson et al., 2010). However, high expression of is an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative breast cancer (Abdel-Fatah et al., 2013; Honma et al., 2015). Likewise, in prostate cancer, the expression level of Bcl-2 is increased during progression from androgen-dependent to androgen-independent growth stage (Lin et al., 2007; McDonnell et al., 1992). In this context, the survival advantage provided by overexpression, facilitate the accumulation of additional lesions that may lead to full malignant transformation. transgenic mice, show accumulation of B lymphoid cells, but the incidence of lymphoma is low and delayed (McDonnell et al., 1989) while Myc transgenic mice develop lymphomas, but only after the 6th week of age and following a period of benign lymphocytosis (Harris et al., 1988; Langdon et al., 1986), double transgenics for Bcl-2 and c-Myc, show a very rapid lymphoma development, caused by the combination of Myc-driven enhanced proliferation, with the Bcl-2-driven apoptosis evasion (Strasser et al., 1990). To generate an effective anti-Bcl-2 compound is essential to understand its mechanism of action. High expression of protect cells from the effects of cellular stresses that would otherwise induce apoptosis (Fulda, 2010; Fulda et al., 2010). The mechanism can be summarized as Bcl-2 binding and inactivating Bcl-2-related proteins which would trigger Cimetropium Bromide apoptosis by damaging the mitochondrial outer membrane (Kroemer et al., 2007). Bcl-2 related proteins contain highly conserved homology (BH) domains and are divided in 3 subgroups (Gillies and Kuwana, 2014): (1) Apoptosis initiators, or BH3 proteins, such as Bim, Bid, Puma and Bad, which detect cellular stress and activate apoptosis; (2) Apoptosis effectors, or multi-BH proteins, such as Bax or Bak, which permeabilize the mitochondrial outer membrane; and (3) Antiapoptotic members, such as Bcl-2 Mcl-1, Bcl-xl, Bfl-1/a1, Bcl-w, Bcl-b, which bind and inactivate BH3 and multi-BH proteins to halt apoptosis. This system is designed to finely regulate apoptosis initiation by inducing or inhibiting Bak and Bax in response to cell conditions. Thus, maintaining the correct balance in the RNF57 expression of all these proteins is essential to ensure apoptosis activation in response to cell damage. The observation that overexpression prevents apoptosis by binding to BH3-protein, led to the generation of BH3-mimetic compounds that would hinder Bcl-2 to allow apoptosis initiation (Hata et al., 2015). It took over 20 years from our discoveries on and 11 years after the elucidation of its microRNA-driven dysregulation mechanism in CLL,.