Browsing by Author "Chachoua, Ilyas"

Now showing 1 - 4 of 4

Open Access
Non-coding RNAs as emerging players in the development, diagnosis, and treatment of cancer
(Frontiers Research Foundation, 2024-07-23) Golla, Upendarrao; Chachoua, Ilyas
Open Access
Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation
(Nature Research, 2023-04-05) Papadopoulos, N.; Nédélec, A.; Derenne, A.; Şulea, T. A.; Pecquet, C.; Chachoua, Ilyas; Vertenoeil, G.; Tilmant, T.; Petrescu, A.; Mazzucchelli, G.; Iorga, B. I.; Vertommen, D.; Constantinescu, S. N.
Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation. Here, we identify the basis of the acquired specificity of CALR mutants for TpoR and define the mechanisms by which complex formation triggers TpoR dimerization and activation. Our work reveals that CALR mutant C-terminus unmasks CALR N-terminal domain, rendering it more accessible to bind immature N-glycans on TpoR. We further find that the basic mutant C-terminus is partially α-helical and define how its α-helical segment concomitantly binds acidic patches of TpoR extracellular domain and induces dimerization of both CALR mutant and TpoR. Finally, we propose a model of the tetrameric TpoR-CALR mutant complex and identify potentially targetable sites. © 2023, The Author(s).
Open Access
Recent advances towards the understanding of secondary acute myeloid leukemia progression
(MDPI AG, 2024-02-27) Auerbach, Scott; Puka, Beana; Golla, Upendarrao; Chachoua, Ilyas
Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies. The genetic aberrations that are associated with sAML affect genes involved in processes such as splicing, chromatin modification and genome integrity. Moreover, non-coding RNAs’ emerged as an important contributing factor to leukemogenesis. For decades, the standard treatment for secondary AML has been the 7 + 3 regimen of cytarabine and daunorubicin which prolongs survival for several months, but modifications in either dosage or delivery has significantly extended that time. Apart from traditional chemotherapy, hematopoietic stem cell transplantation, CAR-T cell therapy and small molecule inhibitors have also emerged to treat sAML.
Open Access
Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms
(Elsevier, 2023-02-23) Pecquet, C.; Papadopoulos, N.; Balligand, T.; Chachoua, Ilyas; Tisserand, A.; Vertenoeil, G.; Nédélec, A.; Vertommen, D.; Roy, A.; Marty, C.; Nivarthi, H.; Defour, J.-P.; El-Khoury, M.; Hug, E.; Majoros, A.; Xu, E.; Zagrijtschuk, O.; Fertig, T. J.; Marta, D. S.; Gisslinger, H.; Gisslinger, B.; Schalling, M.; Casetti, I.; Rumi, E.; Pietra, D.; Cavalloni, C.; Arcaini, L.; Cazzola, M.; Komatsu, N.; Kihara, Y.; Sunami, Y.; Edahiro, Y.; Araki, M.; Lesyk, R.; Buxhofer-Ausch, V.; Heibl, S.; Pasquier, F.; Havelange, V.; Plo, I.; Vainchenker, W.; Kralovics, R.; Constantinescu, S. N.
Mutant calreticulin (CALR) proteins resulting from a −1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene. © 2023 The American Society of Hematology.