intracellular-phosphoflow-cytometry-acute-myeloid-leukemia-patient

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

To adapt and resist approved treatments, acute myeloid leukemia (AML) cells activate specific molecular pathways that lead to changes in gene expression, ...

Lady Davis Institute for Medical Research

PARP-3 is member of the PARP family of poly (ADP-ribose) polymerases involved in ADPribosylation. PARPs are involved in the basic mechanisms of DNA repair. PARP3, a critical player for efficient mitotic progression, is required for the stabilization of the mitotic spindle by regulation of the mitotic components, NuMA and Tankyrase 1.

PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines.

In this work we explored metabolic aspects of human primary leukemic lymphocytes that hold a potential impact on the treatment of Bruton tyrosine kinase (BTK)-driven diseases. Our results suggest that there is crosstalk between Bruton tyrosine kinase (BTK) signaling and bioenergetic stress responses. In primary chronic lymphocytic leukemia (CLL) lymphocytes, pharmacological interference with mitochondrial ATP synthesis or glucose metabolism affects BTK activity. Conversely, an inhibitor of BTK used clinically (ibrutinib) induces bioenergetic stress responses that in turn affect ibrutinib resistance. Although the detailed molecular mechanisms are still to be defined, our work shows for the first time that in primary B cells, metabolic stressors enhance BTK signaling and suggest that metabolic rewiring to hyperglycemia affects ibrutinib resistance in TP53 deficient chronic lymphocytic leukemia (CLL) lymphocytes.

Bruton's tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes.

Poly(ADP-ribose) polymerases 1 and 2 (PARP1, 2), and 3 mediate protein modifications that facilitate the recruitment of DNA repair factors to single and double strand breaks. PARP3 is unique in that it is also required for efficient mitotic progression and stabilization of the mitotic spindle. Eribulin, an anti-microtubule agent used clinically to treat breast cancer, exerts its cytotoxicity by altering microtubule dynamics resulting in cell cycle arrest and apoptosis. Herein, we hypothesize that the pan PARP inhibitor olaparib has the potential to enhance the cytotoxicity of eribulin by halting mitosis through inhibition of PARP3.

PARP Inhibition Sensitizes Breast Cancer Cells to Eribulin.

For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). However, the antitumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. In this study, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase, Herc1, as a key modulator of Ara-C response in mouse AML models driven by the KMT2A/MLLT3 fusion or by the constitutive coexpression of Hoxa9 and Meis1, both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase as a novel target of Herc1 in both mouse AML models. We observed that HERC1 is overexpressed in AML when compared with other cancer types and that higher HERC1 expression was associated with shorter overall survival in patients with AML in the The Cancer Gene Atlas program (TCGA) and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML.

Article	Year
PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines. Breast cancer research and treatment\| PubMed ID: 30039287	2018
Bruton's tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes. Scientific reports\| PubMed ID: 31363127	2019
PARP Inhibition Sensitizes Breast Cancer Cells to Eribulin. Frontiers in bioscience (Landmark edition)\| PubMed ID: 37005765	2023
The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia. Blood advances\| PubMed ID: 39093953	2024

Bahram Sharif-Askari

Biography

JoVE Journal Publications

Other Publications