المؤلفون: Qing Wei, Sa A. Wang, Sanam Loghavi, Hong Fang, L. Jeffrey Medeiros, Wei Wang

المصدر: eJHaem, Vol 5, Iss 2, Pp 379-382 (2024)

مصطلحات موضوعية: acute myeloid leukemia, immunohistochemistry, NPM1, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Abstract Nucleophosmin 1 (NPM1) mutations occur in approximately one‐third cases of adult de novo acute myeloid leukemia (AML). Identification of NPM1 mutations is important for classification, risk stratification, tailored therapy, and monitoring minimal residual disease. Mutational analysis is widely used for detecting NPM1 mutations. Immunochemistry assessing abnormal cytoplasmic localization of NPM1 protein has been used as a surrogate marker for NPM1 mutations. We present a case of AML with mutated NPM1 that was missed by sequencing analysis but detected by immunohistochemistry. This case highlights the value of immunohistochemistry in identifying NPM1 mutations in a subset of AML cases.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2688-6146Test

الوصول الحر: https://doaj.org/article/7ca035fc4517481587956fc20e45efb4Test

المؤلفون: Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Del Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T. Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero, Simona Colla

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-5 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs’ survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/f8ae8a5e42764717965abbcac1ae14a5Test

المؤلفون: Christopher P. Mill, Warren C. Fiskus, Courtney D. DiNardo, Patrick Reville, John A. Davis, Christine E. Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D. Khoury, Kapil N. Bhalla

المصدر: Blood Cancer Journal, Vol 14, Iss 1, Pp 1-12 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2044-5385Test

الوصول الحر: https://doaj.org/article/b9424549a1ed49b58740fad27c6be69cTest

المؤلفون: Alex Bataller, Hagop Kantarjian, Alexandre Bazinet, Tapan Kadia, Naval Daver, Courtney D. DiNardo, Gautam Borthakur, Sanam Loghavi, Keyur Patel, Guilin Tang, Koji Sasaki, Nicholas J. Short, Musa Yilmaz, Ghayas C. Issa, Yesid Alvarado, Guillermo Montalban-Bravo, Abhishek Maiti, Hussein A. Abbas, Koichi Takahashi, Sherry Pierce, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi

المصدر: Haematologica, Vol 999, Iss 1 (2024)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.

وصف الملف: electronic resource

العلاقة: https://haematologica.org/article/view/11576Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test

الوصول الحر: https://doaj.org/article/933107ee2d9a47c0ad4b8d730636ebc4Test

المؤلفون: Cristina A. Tentori, Lin P. Zhao, Benedetta Tinterri, Kathryn E. Strange, Katharina Zoldan, Konstantinos Dimopoulos, Xingmin Feng, Elena Riva, Benjamin Lim, Yannick Simoni, Vidhya Murthy, Madeline J. Hayes, Antonella Poloni, Eric Padron, Bruno A. Cardoso, Michael Cross, Susann Winter, Aida Santaolalla, Bhavisha A. Patel, Emma M. Groarke, Daniel H. Wiseman, Katy Jones, Lauren Jamieson, Charles Manogaran, Naval Daver, Laura Gallur, Wendy Ingram, P. Brent Ferrell, Katja Sockel, Nicolas Dulphy, Nicolas Chapuis, Anne S. Kubasch, Astrid M. Olsnes, Austin Kulasekararaj, Hugues De Lavellade, Wolfgang Kern, Mieke Van Hemelrijck, Dominique Bonnet, Theresia M. Westers, Sylvie Freeman, Uta Oelschlaegel, David Valcarcel, Marco G. Raddi, Kirsten Grønbæk, Michaela Fontenay, Sanam Loghavi, Valeria Santini, Antonio M. Almeida, Jonathan M. Irish, David A. Sallman, Neal S. Young, Arjan A. van deLoosdrecht, Lionel Adès, Matteo G. Della Porta, Catherine Cargo, Uwe Platzbecker, Shahram Kordasti, i4MDS consortium

المصدر: HemaSphere, Vol 8, Iss 5, Pp n/a-n/a (2024)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Abstract Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2572-9241Test

الوصول الحر: https://doaj.org/article/03709a016c294b7a852299f195f68f9bTest

المؤلفون: Danielle Hammond, Sanam Loghavi, Sa A. Wang, Marina Y. Konopleva, Tapan M. Kadia, Naval G. Daver, Maro Ohanian, Ghayas C. Issa, Yesid Alvarado, Nicholas J. Short, Koji Sasaki, Naveen Pemmaraju, Guillermo Montalban-Bravo, Curtis A. Lachowiez, Abhishek Maiti, Guillermo Garcia-Manero, Elias J. Jabbour, Gautam Borthakur, Farhad Ravandi, Koichi Takahashi, Sherry R. Pierce, Hagop M. Kantarjian, Courtney D. DiNardo

المصدر: Blood Cancer Journal, Vol 13, Iss 1, Pp 1-4 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2044-5385Test

الوصول الحر: https://doaj.org/article/b7c6599d1ff945fc8f42960c8b15f42eTest

المؤلفون: Gokce Toruner, Zhenya Tang, Shimin Hu, Sanam Loghavi, Rashmi Kanagal Shamanna, L. Jeffrey Medeiros, Guilin Tang

المصدر: Genetics in Medicine Open, Vol 2, Iss , Pp 101489- (2024)

مصطلحات موضوعية: Genetics, QH426-470, Medicine

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2949774424006356Test; https://doaj.org/toc/2949-7744Test

الوصول الحر: https://doaj.org/article/ba02282098294e3a81fe8a3e8e5f86caTest

المؤلفون: Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A. Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C. Issa, Samuel I. Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J. Jabbour, Steven M. Kornblau, Nicholas J. Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M. Kantarjian, Michael Andreeff, Courtney D. DiNardo

المصدر: Blood Cancer Journal, Vol 13, Iss 1, Pp 1-6 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23–80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1–7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2044-5385Test

الوصول الحر: https://doaj.org/article/e09e6500217f443ab08d9d78cb583310Test

المؤلفون: Hagop Kantarjian, Fadi G. Haddad, Nitin Jain, Koji Sasaki, Nicholas J. Short, Sanam Loghavi, Rashmi Kanagal-Shamanna, Jeffrey Jorgensen, Issa Khouri, Partow Kebriaei, Yesid Alvarado, Tapan Kadia, Shilpa Paul, Guillermo Garcia-Manero, Bouthaina Dabaja, Musa Yilmaz, Jovitta Jacob, Rebecca Garris, Susan O’Brien, Farhad Ravandi, Elias Jabbour

المصدر: Journal of Hematology & Oncology, Vol 16, Iss 1, Pp 1-12 (2023)

مصطلحات موضوعية: Philadelphia-negative ALL, Inotuzumab, Blinatumomab, Chemo-immunotherapy, Salvage, Outcome, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-8722Test

الوصول الحر: https://doaj.org/article/b4f44ab39b2049e6b4e01db67dec5fb5Test

المؤلفون: Bing Z. Carter, Po Yee Mak, Wenjing Tao, Edward Ayoub, Lauren B. Ostermann, Xuelin Huang, Sanam Loghavi, Steffen Boettcher, Yuki Nishida, Vivian Ruvolo, Paul E. Hughes, Phuong K. Morrow, Torsten Haferlach, Steven Kornblau, Muharrem Muftuoglu, Michael Andreeff

المصدر: Blood Cancer Journal, Vol 13, Iss 1, Pp 1-13 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53–wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic–driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2044-5385Test

الوصول الحر: https://doaj.org/article/ed4c5f0838c540e4bdf8c2b8285492dfTest