11 results on '"Kanagal-Shamanna R"'
Search Results
2. Influence of co-mutational patterns in disease phenotype and clinical outcomes of chronic myelomonocytic leukemia.
- Author
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Montalban-Bravo G, Rodriguez-Sevilla JJ, Swanson DM, Kanagal-Shamanna R, Hammond D, Chien K, Sasaki K, Jabbour E, DiNardo C, Takahashi K, Short N, Issa GC, Pemmaraju N, Kadia T, Ravandi F, Daver N, Borthakur G, Loghavi S, Pierce S, Bueso-Ramos C, Kantarjian H, and Garcia-Manero G
- Subjects
- Humans, Prognosis, Male, Female, Aged, Middle Aged, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic pathology, Phenotype, Mutation
- Published
- 2024
- Full Text
- View/download PDF
3. Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.
- Author
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Reinig EF, Rubinstein JD, Patil AT, Schussman AL, Horner VL, Kanagal-Shamanna R, Churpek JE, and Matson DR
- Subjects
- Humans, Genetic Predisposition to Disease, Syndrome, Multiple Organ Failure, Germ-Line Mutation, Leukemia, Myeloid, Acute diagnosis, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics
- Abstract
Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5
th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
- Full Text
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4. Characteristics of patients with myelodysplastic neoplasm and spliceosome mutations.
- Author
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Urrutia S, Li Z, Almanza E, Bataller A, Kanagal-Shamanna R, Senapati J, Sasaki K, Chien K, Montalban-Bravo G, DiNardo C, Borthakur G, Bueso-Ramos C, Pierce S, Kantarjian H, and Garcia-Manero G
- Subjects
- Humans, Spliceosomes genetics, Spliceosomes metabolism, Mutation, RNA Splicing genetics, RNA Splicing Factors genetics, RNA Splicing Factors metabolism, Neoplasms, Myelodysplastic Syndromes genetics
- Published
- 2023
- Full Text
- View/download PDF
5. High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance.
- Author
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Yang H, Garcia-Manero G, Sasaki K, Montalban-Bravo G, Tang Z, Wei Y, Kadia T, Chien K, Rush D, Nguyen H, Kalia A, Nimmakayalu M, Bueso-Ramos C, Kantarjian H, Medeiros LJ, Luthra R, and Kanagal-Shamanna R
- Subjects
- Chromosome Banding, Chromosome Mapping, Homeodomain Proteins, Humans, Prognosis, Chromosome Aberrations, Myelodysplastic Syndromes
- Abstract
Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique for high-resolution genome-wide SV profiling (SVP). We explored the clinical value of SVP by OGM in 101 consecutive, newly diagnosed MDS patients from a single-center, who underwent standard-of-care cytogenetic and targeted NGS studies. OGM detected 383 clinically significant, recurrent and novel SVs. Of these, 224 (51%) SVs, seen across 34% of patients, were cryptic by CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). SVP decreased the proportion of normal karyotype by 16%, identified complex genomes (17%), chromothripsis (6%) and generated informative results in both patients with insufficient metaphases. Precise gene/exon-level mapping allowed assessment of clinically relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. SV data was complementary to NGS. When applied in retrospect, OGM results changed the comprehensive cytogenetic scoring system (CCSS) and R-IPSS risk-groups in 21% and 17% patients respectively with an improved prediction of prognosis. By multivariate analysis, CCSS by OGM only (not CBA), TP53 mutation and BM blasts independently predicted survival. This is the first and largest study reporting the value of combined SVP and NGS for MDS prognostication., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
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6. Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia.
- Author
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Wei Y, Kanagal-Shamanna R, Zheng H, Bao N, Lockyer PP, Class CA, Darbaniyan F, Lu Y, Lin K, Yang H, Montalban-Bravo G, Ganan-Gomez I, Soltysiak KA, Do KA, Colla S, and Garcia-Manero G
- Subjects
- Animals, Gene Expression Profiling, Genome, Humans, Loss of Function Mutation, Mice, Mutation, Proto-Oncogene Proteins genetics, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dioxygenases deficiency, Dioxygenases genetics, Dioxygenases metabolism, Jumonji Domain-Containing Histone Demethylases biosynthesis, Jumonji Domain-Containing Histone Demethylases genetics, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic metabolism, Leukemia, Myelomonocytic, Juvenile genetics, Leukemia, Myelomonocytic, Juvenile metabolism
- Abstract
Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
7. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.
- Author
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Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, Bejar R, Berti E, Busque L, Chan JKC, Chen W, Chen X, Chng WJ, Choi JK, Colmenero I, Coupland SE, Cross NCP, De Jong D, Elghetany MT, Takahashi E, Emile JF, Ferry J, Fogelstrand L, Fontenay M, Germing U, Gujral S, Haferlach T, Harrison C, Hodge JC, Hu S, Jansen JH, Kanagal-Shamanna R, Kantarjian HM, Kratz CP, Li XQ, Lim MS, Loeb K, Loghavi S, Marcogliese A, Meshinchi S, Michaels P, Naresh KN, Natkunam Y, Nejati R, Ott G, Padron E, Patel KP, Patkar N, Picarsic J, Platzbecker U, Roberts I, Schuh A, Sewell W, Siebert R, Tembhare P, Tyner J, Verstovsek S, Wang W, Wood B, Xiao W, Yeung C, and Hochhaus A
- Subjects
- Humans, World Health Organization, Hematologic Neoplasms, Histiocytosis
- Abstract
The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
8. Marrow ring sideroblasts are highly predictive for TP53 mutation in MDS with excess blasts.
- Author
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Swoboda DM, Kanagal-Shamanna R, Brunner AM, Cluzeau T, Chan O, Al Ali N, Montalban-Bravo G, Gesiotto QJ, Gavralidis A, Hunter AM, Lee JH, Kuykendall AT, Talati C, Sweet KL, Lancet JE, Padron E, Hussaini M, Song J, Garcia-Manero G, Komrokji RS, and Sallman DA
- Subjects
- Humans, Mutation, RNA Splicing Factors genetics, Tumor Suppressor Protein p53 genetics, Anemia, Sideroblastic genetics, Bone Marrow
- Published
- 2022
- Full Text
- View/download PDF
9. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations.
- Author
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Jain N, Thompson P, Burger J, Ferrajoli A, Takahashi K, Estrov Z, Borthakur G, Bose P, Kadia T, Pemmaraju N, Sasaki K, Konopleva M, Jabbour E, Garg N, Wang X, Kanagal-Shamanna R, Patel K, Wang W, Jorgensen J, Wang S, Lopez W, Ayala A, Plunkett W, Gandhi V, Kantarjian H, O'Brien S, Keating M, and Wierda WG
- Subjects
- Adenine administration & dosage, Adenine analogs & derivatives, Adult, Aged, Antibodies, Monoclonal, Humanized administration & dosage, Biomarkers, Tumor, Cyclophosphamide administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Piperidines administration & dosage, Prognosis, Survival Rate, Tumor Suppressor Protein p53 genetics, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Mutation, Tumor Suppressor Protein p53 metabolism
- Abstract
Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
- Full Text
- View/download PDF
10. Activity of venetoclax-based therapy in chronic myelomonocytic leukemia.
- Author
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Montalban-Bravo G, Hammond D, DiNardo CD, Konopleva M, Borthakur G, Short NJ, Ramos-Perez J, Guerra V, Kanagal-Shamanna R, Naqvi K, Sasaki K, Jabbour E, Pemmaraju N, Kadia TM, Ravandi F, Daver N, Estrov Z, Pierce S, Kantarjian H, and Garcia-Manero G
- Subjects
- Adult, Aged, Aged, 80 and over, Female, High-Throughput Nucleotide Sequencing methods, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Myelomonocytic, Chronic genetics, Male, Middle Aged, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Antineoplastic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Myelomonocytic, Chronic drug therapy, Sulfonamides therapeutic use
- Published
- 2021
- Full Text
- View/download PDF
11. Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes.
- Author
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Montalban-Bravo G, Class CA, Ganan-Gomez I, Kanagal-Shamanna R, Sasaki K, Richard-Carpentier G, Naqvi K, Wei Y, Yang H, Soltysiak KA, Chien K, Bueso-Ramos C, Do KA, Kantarjian H, and Garcia-Manero G
- Subjects
- Aged, Antigens, CD34 metabolism, Bone Marrow metabolism, Disease Progression, Female, Humans, Inflammation, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic metabolism, Male, Middle Aged, Myelodysplastic Syndromes metabolism, Phenotype, Prognosis, Protein Kinases metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Myelodysplastic Syndromes diagnosis, Necroptosis, Transcriptome
- Abstract
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n = 46) or after (n = 18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-Seq. Compared with healthy controls, expression levels of MLKL (CMML: 2.09 log2FC, p = 0.0013; MDS: 1.89 log2FC, p = 0.003), but not RIPK1 or RIPK3, were significantly upregulated. Higher expression levels of MLKL were associated with lower hemoglobin levels at diagnosis (-0.19 log2FC per 1 g/dL increase of Hgb, p = 0.03). Significant reduction in MLKL levels was observed after HMA therapy (-1.06 log2FC, p = 0.05) particularly among nonresponders (-2.89 log2FC, p = 0.06). Higher RIPK1 expression was associated with shorter survival (HR 1.92, 95% CI 1.00-3.67, p = 0.049 by Cox proportional hazards). This data provides further support for a role of necroptosis in MDS, and potentially response to HMAs and prognosis. This data also indicate that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS.
- Published
- 2020
- Full Text
- View/download PDF
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