Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature.

Decoding Acute Myeloid Leukemia: A Clinician's Guide to Functional Profiling.

Acute myeloid leukemia (AML) is a complex clonal disorder characterized by clinical, genetic, metabolomic, and epigenetic heterogeneity resulting in the uncontrolled proliferation of aberrant blood-forming precursor cells. Despite advancements in the understanding of the genetic, metabolic, and epigenetic landscape of AML, it remains a significant therapeutic challenge. Functional profiling techniques, such as BH3 profiling (BP), gene expression profiling (GEP), proteomics, metabolomics, drug sensitivity/resistance testing (DSRT), CRISPR/Cas9, and RNAi screens offer valuable insights into the functional behavior of leukemia cells.

Mitochondria and Acute Leukemia: A Clinician's Perspective.

Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival.

Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.

Unlabelled: In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML.

Therapeutic biomarkers in acute myeloid leukemia: functional and genomic approaches.

Acute myeloid leukemia (AML) is clinically and genetically a heterogeneous disease characterized by clonal expansion of abnormal hematopoietic progenitors. Genomic approaches to precision medicine have been implemented to direct targeted therapy for subgroups of AML patients, for instance, IDH inhibitors for mutated patients, and FLT3 inhibitors with mutated patients. While next generation sequencing for genetic mutations has improved treatment outcomes, only a fraction of AML patients benefit due to the low prevalence of actionable targets.

Physicochemical Significance of Topological Indices: Importance in Drug Discovery Research.

Background: Quantitative Structure-Activity Relationship (QSAR) studies describing the correlations between biological activity as dependent parameters and physicochemical and structural descriptors, including topological indices (TIs) as independent parameters, play an important role in drug discovery research. The emergence of graph theory in exploring the structural attributes of the chemical space has led to the evolution of various TIs, which have made their way into drug discovery. The TIs are easy to compute compared to the empirical parameters, but they lack physiochemical interpretation, which is essential in understanding the mechanism of action.