Citations 2
A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease
Molitor, Anne , Lederle, Alexandre , Radosavljevic, Mirjana , Sapuru, Vinay , Thomas, Megan E. Zavorka, Yang, Jianying , Shirin, Mahsa , Collin-Bund, Virginie , Jeřábková, Kateřina , Miao, Zhichao , Bernard, Alice , Grenot, Pierre , Lewis, Elyssa G., Person, Richard, Esperón-Moldes, Uxía-Saraiva, Kaare, Milja, Nokelainen, Pekka, Batzir, Nurit Assia , Hoffer, Gal Zaks, Stemmelen, Tristan , Naegely, Lydie , Hanauer, Antoine , Bibi‐Triki, Sabrina , Grün, Sarah, Jung, Sophie , Busnelli, Ignacio, Tripolszki, Kornélia , Ordoñez, Natalia, Song, Eunkyung , Zajo, Kristin , Partida‐Sánchez, Santiago , Robledo‐Avila, Frank , Kumánovics, Attila , Pichot, Angélique , Toker, Ori , Mejía, César , Parvaneh, Nima , Knapp, Esther , Hersh, Joseph H., Kenney, Heather , Bajwa, Rajinder , Thomas, Caroline , Ehl, Stephan , Isidor, Bertrand , Abraham, Roshini S. , Hite, Richard K. , Bertoli‐Avella, Aida M. , Bahram, Seiamak , Zavorka Thomas, Megan E , Jerabkova-Roda, Katerina , Rolli, Véronique , Grenot, Pierre , Castro, Carla Noemi , Rosenzwajg, Michelle , Person, Richard , Batzir, Nurit Assia , Hoffer, Gal Zaks , Paul, Nicodème , Stemmelen, Tristan , Naegely, Lydie , Hanauer, Antoine , Bibi-Triki, Sabrina , Jung, Sophie , Bauer, Peter , Zajo, Kristin , Partida-Sanchez, Santiago , Robledo-Avila, Frank , Kumanovics, Attila , Louzoun, Yoram , Hirschler, Aurélie , Pichot, Angélique , Toker, Ori , Mejía, Cesar Andrés Muñoz , Parvaneh, Nima , Knapp, Esther , Delmonte, Ottavia M , Notarangelo, Luigi D , Goetz, Jacky G , Kahwash, Samir B , Carapito, Christine , Bajwa, Rajinder P S , Thomas, Caroline , Ehl, Stephan , Isidor, Bertrand , Carapito, Raphael , Abraham, Roshini S , Hite, Richard K , Bahram, Seiamak , Esperón-Moldes, Uxia , Al‐Ali, Ruslan , Kenney, Heather , Kahwash, Samir B. , Marcus, Nufar
Science Advances | September 13, 2024 | Volume: 10 | Issue: 37 | Pages: No page available
Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ITPR1 ), 2 ( ITPR2 ), and 3 ( ITPR3 ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant—NM_002224.3:c.7570C>T, p.Arg2524Cys—causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 + lymphopenia, a quasi-absence of naïve CD4 + and CD8 + cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg 2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.
RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106
Chen, Robert W., Bernstein, Steven H., Kahwash, Samir B. , Forman, Stephen J. , Shea, Thomas C., Cashen, Amanda F. , Blum, Kristie A. , Fenske, Timothy S. , Fisher, Richard I., Cheson, Bruce D. , Smith, Sonali M. , Faham, Malek, Wilkins, Jennifer, Leonard, John P. , Friedberg, Jonathan W. , Li, Hongli , Rimsza, Lisa M. , Constine, Louis S , Barr, Paul M. , Phillips, Tycel , LeBlanc, Michael , Kahl, Brad S. , Kahwash, Samir B
British Journal of Haematology | December 19, 2016 | Volume: 176 | Issue: 5 | Pages: 759-769
SummaryAggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto‐HCT. Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL. RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL.