Biology subjects

Piechaczyk, M.

Publications and source records attributed to Piechaczyk, M..

3 recordsLinked to original sources

bioRxiv2021

The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of Acute Myeloid Leukemias

Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox (CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0-M2 ones. Using a gene expression-based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic-based risk classification, in AML patients.

cancer biology↗

bioRxiv2019

Ubiquitin and SUMO conjugation as biomarkers of Acute Myeloid Leukemias response to chemotherapies

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cells response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict Acute Myeloid Leukemias (AML) response to standard chemotherapy (daunorubicine-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9000 proteins spotted on protein-arrays. We identified 122 proteins whose conjugation by these post-translational modifiers marks AML resistance to DNR and/or Ara-C. Based on this modifomic signature, we defined a statistical score able to predict AML patient response to standard chemotherapy. We finally developed a miniaturized assay to easily assess the modification level of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patients response to treatments.\n\nSummary blurbThis study describes the identification of a new class of biomarkers of cancer response to therapies based on protein modification by Ubiquitin and SUMO and provides the tools to analyze them in Acute Myeloid Leukemia patient samples.

cancer biology↗

bioRxiv2018

Targeting the SUMO pathway primes all-trans-retinoic acid-induced differentiation of non promyelocytic Acute Myeloid Leukemias

Differentiation therapies using All-trans-retinoic acid (ATRA) are highly efficient at treating Acute Promyelocytic Leukemia (APL), a minor subtype of Acute Myeloid Leukemias (AML). However, their efficacy, if any, is very limited in the case of non-APL AMLs. We report here that the inhibition of SUMOylation, a post-translational modification related to ubiquitinylation, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AMLs. Controlled inhibition of SUMOylation with pharmacological inhibitors (2-D08 or anacardic acid), or via overexpression of SENP desumoylases, strongly enhances the ATRA-induced expression of key genes involved in differentiation, proliferation and apoptosis in non-APL AML cells. This activates ATRA-induced terminal myeloid differentiation and reduces cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation by overexpressing the SUMO-conjugating enzyme Ubc9 dampens the expression of ATRA-responsive genes and prevents differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor prognosis cancer, which has not significantly changed over the past 40 years.

cancer biology↗