Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways.
Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B‑cell lymphoma‑2 (Bcl‑2)‑associated death promoter phosphorylation at Ser112.
Tet methylcytosine dioxygenase (Tet2), B-cell lymphoma 2 (Bcl2), and solute carrier family 23 member 2 (Slc23a2) are the major target genes in the treatment of leukemia and are relevant to vitamin C.
The characteristic high-level expression of BCL2 in CLL that can enhance leukemia-cell survival has now become an Achilles heel targeted by clinically effective drugs such as venetoclax.
Venetoclax (ABT-199/GDC-0199) is a highly selective bioavailable inhibitor of BCL-2 protein, which is more effective and less valid against BCL-xL in BCL2-dependent leukemia and lymphoma cell.
New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody-drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia.
The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML) (Kaufmann et al., 2016) and acute lymphocytic leukemia (ALL) (Findley, Gu, Yeager, & Zhou, 1997), suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse.
These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.
The protein expression levels of B‑cell lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) were also compared between transfected and wild‑type HLE‑B3 cells by western blot analysis.
We previously developed cell-penetrating VDAC1-derived peptides that interact with hexokinase (HK), Bcl-2, and Bcl-xL to prevent the anti-apoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma.
They could markedly down-regulate the expressions of the c-Myc, Bcl-2 and CDK6 oncogenes in MV4-11 in the qRT-PCR and western blot studies, which further demonstrated that compound 1 and its derivatives could serve as a promising therapeutic strategy for MLL leukemia by targeting BRD4_BD1 protein.
Sorafenib-related IL-15 production caused an increase in CD8<sup>+</sup>CD107a<sup>+</sup>IFN-γ<sup>+</sup> T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients.
We found statistically significant increase in mRNA expression of all investigated proteins (p53, BAX, Bcl-2 and Bcl-XL) between the leukemia samples and leukocytes from healthy volunteers.
Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.<b>Significance:</b> Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease.<i></i>.
Thus, inhibition of anti-apoptotic BCL-2 family proteins has been proposed as a possible antineoplastic strategy, and BCL-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung cancer.
Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia.
Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism.
We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells.
Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1.
BLI and PB were subsequently used to evaluate efficacy of the Bcl-2 inhibitor venetoclax.<b>Results:</b> BLI considerably accelerated and enhanced detection of leukemia burden compared with PB and identified sites of residual disease during treatment in a quantitative manner, highlighting limitations in current PB-based scoring criteria.