Blood Cancer Journal

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NPM-ALK mediates phosphorylation of MSH2 at tyrosine 238, creating a functional deficiency in MSH2 and the loss of mismatch repair
Blood Cancer Journal - Tập 5 Số 5 - Trang e311-e311
Kathleen M. Bone, P Wang, Fang Wu, Chenming Wu, L Li, Julinor Bacani, Susan E. Andrew, Rai‐Hua Lai
AbstractThe vast majority of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ALCL) tumors express the characteristic oncogenic fusion protein NPM-ALK, which mediates tumorigenesis by exerting its constitutive tyrosine kinase activity on various substrates. We recently identified MSH2, a protein central to DNA mismatch repair (MMR), as a novel binding partner and phosphorylation substrate of NPM-ALK. Here, using liquid chromatography–mass spectrometry, we report for the first time that MSH2 is phosphorylated by NPM-ALK at a specific residue, tyrosine 238. Using GP293 cells transfected with NPM-ALK, we confirmed that the MSH2Y238F mutant is not tyrosine phosphorylated. Furthermore, transfection of MSH2Y238F into these cells substantially decreased the tyrosine phosphorylation of endogenous MSH2. Importantly, gene transfection of MSH2Y238F abrogated the binding of NPM-ALK with endogenous MSH2, re-established the dimerization of MSH2:MSH6 and restored the sensitivity to DNA mismatch-inducing drugs, indicative of MMR return. Parallel findings were observed in two ALK+ALCL cell lines, Karpas 299 and SUP-M2. In addition, we found that enforced expression of MSH2Y238F into ALK+ALCL cells alone was sufficient to induce spontaneous apoptosis. In conclusion, our findings have identified NPM-ALK-induced phosphorylation of MSH2 at Y238 as a crucial event in suppressing MMR. Our studies have provided novel insights into the mechanism by which oncogenic tyrosine kinases disrupt MMR.
Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts
Blood Cancer Journal - Tập 6 Số 8 - Trang e458-e458
Marc Cartellieri, Anja Feldmann, Stefanie Koristka, Claudia Arndt, Simon Loff, Armin Ehninger, Malte von Bonin, Elham Pishali Bejestani, Gerhard Ehninger, Michael Bachmann
AbstractThe adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept’ for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.
Differences in genomic patterns and clinical outcomes between African-American and White patients with myelodysplastic syndromes
Blood Cancer Journal - Tập 7 Số 9 - Trang e602-e602
Aziz Nazha, Karam Al-Issa, B Przychodzen, Nour Abuhadra, Cassandra M. Hirsch, Jaroslaw P. Maciejewski, Mikkael A. Sekeres
Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors
Blood Cancer Journal - Tập 6 Số 9 - Trang e469-e469
Geoffroy Venton, Mileidys Pérez‐Alea, Céline Baier, Guy Fournet, G Quash, Yasmine Labiad, G Martín, F. Sanderson, Pascale Poullin, Pierre Suchon, Laure Farnault, Cong Tu Nguyen, C. L. Brunet, İsmail Çeylan, Régis Costello
AbstractThe vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38− leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38− subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.
Final results of a phase 1b study of the safety and efficacy of the PI3Kδ inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies
Blood Cancer Journal - Tập 8 Số 2
Arnon P. Kater, Sanne H. Tonino, Menno Spiering, Martine E.D. Chamuleau, Roberto Liu, Adeboye H. Adewoye, Jun Gao, Lyndah Dreiling, Yan Xin, Jeanette K. Doorduijn, Marie José Kersten
Myelofibrosis Treatment Algorithm 2018
Blood Cancer Journal - Tập 8 Số 8
Ayalew Tefferi, Paola Guglielmelli, Animesh Pardanani, Alessandro M. Vannucchi
AbstractTwo novel prognostic systems for primary myelofibrosis (PMF) were recently unveiled: GIPSS (genetically inspired prognostic scoring system) and MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients). GIPSS is based exclusively on genetic markers: mutations and karyotype. MIPSS70 includes mutations and clinical risk factors. In its most recent adaptation, the prognostic value of MIPSS70 has been bolstered by the inclusion of a three-tiered cytogenetic risk stratification and use of hemoglobin thresholds that are adjusted for sex and severity (MIPSS70+ version 2.0). GIPSS features four, MIPSS70 three, and MIPSS70+ version 2.0 five risk categories. MIPSS70 is most useful in the absence of cytogenetic information. MIPSS70+ version 2.0 is more comprehensive than MIPSS70 and is the preferred model in the presence of cytogenetic information. Both MIPSS70 and MIPSS70+ version 2.0 require an online score calculator (http://www.mipss70score.it). GIPPS offers a lower complexity prognostic tool that reliably identifies candidates for allogeneic stem cell transplant (GIPSS high-risk disease) or long-term observation with little or no therapeutic intervention (GIPSS low-risk disease). Ultimately, we favor a step-wise prognostication approach that starts with GIPSS but also considers MIPSS70+ version 2.0 for confirming the most appropriate treatment approach for the individual patient.
Different effect of hydroxyurea and phlebotomy on prevention of arterial and venous thrombosis in Polycythemia Vera
Blood Cancer Journal - Tập 8 Số 12
Tiziano Barbui, Valerio De Stefano, Arianna Ghirardi, Arianna Masciulli, Guido Finazzi, Alessandro M. Vannucchi
Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases
Blood Cancer Journal - Tập 8 Số 11
Valerio De Stefano, Elena Rossi, Alessandra Carobbio, Arianna Ghirardi, Silvia Betti, Guido Finazzi, Alessandro M. Vannucchi, Tiziano Barbui
AbstractWe collected 1500 patients with myeloproliferative neoplasms (MPN) and arterial or venous thrombosis (935/565), pooling three independent cohorts previously reported. Long-term treatment with antiplatelet drugs or vitamin K-antagonists (VKA) was given to 1391 (92.7%) patients; 975 (65%) patients received hydroxyurea (HU). We recorded 348 recurrences (venous in 142 cases) over 6075 patient-years, with an incidence rate of 5.7 per 100 pt-years (95% CI 5.1–6.4). The site of the first thrombosis predicted the site of recurrence. Independent factors influencing the rate of novel arterial thrombosis were HU (HR 0.67, 95% CI 0.46–0.98), antiplatelet treatment (HR 0.54, 95% CI 0.35–0.82), and VKA (HR 0.58, 95% CI 0.35–0.96). On the contrary, the recurrence of venous thromboses was significantly diminished only by VKA (HR 0.60, 95% CI 0.37–0.95), while HU prevented late but not early recurrences after venous thrombosis at common sites. Of note, we failed to demonstrate a positive effect of HU in the prevention of recurrent splanchnic vein thrombosis. In conclusion, in MPN patients, HU plays a role in the prevention of arterial thrombosis, together with aspirin and VKA, whereas its action in the prevention of recurrent venous thrombosis is uncertain. Such findings call for future studies to optimize and personalize secondary prophylaxis after MPN-related thrombosis.
Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins
Blood Cancer Journal - Tập 7 Số 1 - Trang e517-e517
Niels Ødum, Lise M. Lindahl, Mette Wod, Thorbjørn Krejsgaard, Axel Skytthe, Anders Woetmann, Lars Iversen, Kaare Christensen
Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome
Blood Cancer Journal - Tập 10 Số 5
Andreas Willerslev-Olsen, Terkild B. Buus, Claudia Nastasi, Edda Blümel, Maria Gluud, Charlotte M. Bonefeld, Carsten Geisler, Lise M. Lindahl, Maarten H. Vermeer, Mariusz A. Wasik, Lars Iversen, Jürgen C. Becker, Mads Hald Andersen, Lise Mette Rahbek Gjerdrum, Ivan V. Litvinov, Thomas Litman, Thorbjørn Krejsgaard, Anders Woetmann, Niels Ødum
AbstractSézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as,Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.
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