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Julia E Maxson - One of the best experts on this subject based on the ideXlab platform.
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outgrowth of a csf3r mutant clone drives a second myeloproliferative neoplasm in a Chronic myeloid Leukemia patient a case report
Biomarker research, 2021Co-Authors: Sarah A Carratt, Diana Brewer, Julia E Maxson, Brian J Druker, Theodore P BraunAbstract:BACKGROUND Chronic myeloid Leukemia (CML) and Chronic Neutrophilic Leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling. CASE PRESENTATION Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of Chronic myeloid Leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, Neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient. CONCLUSIONS This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
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CML: implications for diagnosis and treatment
2016Co-Authors: Jason Gotlib, Julia E Maxson, Tracy I. George, Jeffrey W. TynerAbstract:new genetics of Chronic Neutrophilic Leukemia and atypica
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the colony stimulating factor 3 receptor t640n mutation is oncogenic sensitive to jak inhibition and mimics t618i
Clinical Cancer Research, 2016Co-Authors: Julia E Maxson, Jason Gotlib, Samuel B Luty, Jason D Macmaniman, Melissa L Abel, Samantha L Savage, Jason C Paik, Peter L Greenberg, Swaleh Bahamadi, Christopher A EideAbstract:Purpose: Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of Chronic Neutrophilic Leukemia (CNL) and a smaller percentage of atypical Chronic myeloid Leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target. Experimental Design: Sanger sequencing of Leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay. Results: Here, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation—despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I. Conclusions: Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML. Clin Cancer Res; 22(3); 757–64. ©2015 AACR .
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csf3r mutations represent a novel therapeutic target in pediatric aml with a high degree of overlap with cebpa mutations a report from cog aaml0531 and cog nci target aml initiative
Blood, 2015Co-Authors: Julia E Maxson, Rhonda E Ries, Yicheng Wang, Robert B Gerbing, Anders E Kolb, Sarah L Thompson, Jaime Guidry M Auvil, Marco A Marra, Stuart Zong, Andrew J MungallAbstract:Activating mutations in Colony Stimulating Factor 3 Receptor (CSF3R, aka GCSFR) are present in ~80% of patients with Chronic Neutrophilic Leukemia (CNL) Despite the high frequency of these mutations in CNL, they are quite rare in adult acute myeloid Leukemia (AML), in which only a single CSF3R mutated case was found in the TCGA AML analysis (0.5%). We have previously demonstrated significant variation in genomic variants between pediatric and adult malignancies, thus prevalence of genomic variants identified in adults need be fully characterized in children. As part of COG/NCI TARGET AML initiative we interrogated the genomic makeup of 200 cases of childhood AML (discovery cohort) using whole genome sequencing and performed subsequent frequency determination of the variants in 787 unselected cases from COG AAML0531 (validation cohort). Somatic variants in CSF3R were initially found to be recurrent in the discovery cohort and underwent frequency determination in the validation cohort to establish their prevalence and correlations with clinical characteristics and outcome. Frequency determination of CSF3R mutation in 787 pediatric patients with available CSF3R data from AAML0531 identified 16 distinct CSF3R mutations in 28 patients (3.6%). Somatic mutations in CSF3R identified in pediatric AML included known oncogenic variants mutations such as T618I and T615A, previously identified in adult CNL studies as well as novel truncations of the CSF3R cytoplasmic domain (Q749X, Y767fs, Y787X and P819/820fs), and missense mutations (E149D, A208V, R223Q, E405K, A431V, and Q516K). Interestingly, although CSF3R truncations usually occur along with a T618I or T615A mutation in CNL/aCML, these two mutation categories were mutually exclusive in pediatric AML. Initial correlation of all CSF3R variants with demographic and clinical/laboratory parameters determined that CSF3R variants were less prevalent in younger patients (age 0-2, p=0.039), with significantly higher association with t(8;21) (32% vs. 14%, p=0.012) and CEBPA mutations (35% vs. 5%, p Compared to non-mutated cases, transforming CSF3R variants had a significant association with CEBPA mutations (44% vs. 5%, p CSF3R mutations define a distinct molecular subset of pediatric AML, which could be therapeutically targeted in the future using kinase inhibitors such as ruxolitinib. The oncogenic CSF3R mutations found in pediatric AML are either the same point mutations or similar truncation mutations as seen in CNL, suggesting that other cooperating genomic alterations may be important in directing these distinct diseases. Interestingly, we found that the majority of pediatric AML patients with CSF3R mutation have either a core binding factor alteration (such as t(8;21)) or a mutation in CEBPA. The enrichment of CEBPA mutations with CSF3R mutations is particularly striking, as CEBPA mutations are ~9 fold more frequent in patients with transforming CSF3R mutations than those without. Understanding the role of cooperating genomic alteration in CSF3R-driven myeloid malignancies will be the subject of future work. The authors would like to gratefully acknowledge the important contributions of the late Dr. Robert Arceci to the AML TARGET initiative. Disclosures Radich:Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy.
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ligand independence of the t618i mutation in the colony stimulating factor 3 receptor csf3r protein results from loss of o linked glycosylation and increased receptor dimerization
Journal of Biological Chemistry, 2014Co-Authors: Julia E Maxson, Brian J Druker, Samuel B Luty, Jason D Macmaniman, Melissa L Abel, Jeffrey W. TynerAbstract:Mutations in the CSF3 granulocyte colony-stimulating factor receptor CSF3R have recently been found in a large percentage of patients with Chronic Neutrophilic Leukemia and, more rarely, in other types of Leukemia. These CSF3R mutations fall into two distinct categories: membrane-proximal mutations and truncation mutations. Although both classes of mutation have exhibited the capacity for cellular transformation, several aspects of this transformation, including the kinetics, the requirement for ligand, and the dysregulation of downstream signaling pathways, have all been shown to be discrepant between the mutation types, suggesting distinct mechanisms of activation. CSF3R truncation mutations induce overexpression and ligand hypersensitivity of the receptor, likely because of the removal of motifs necessary for endocytosis and degradation. In contrast, little is known about the mechanism of activation of membrane-proximal mutations, which are much more commonly observed in Chronic Neutrophilic Leukemia. In contrast with CSF3R truncation mutations, membrane-proximal mutations do not exhibit overexpression and are capable of signaling in the absence of ligand. We show that the Thr-615 and Thr-618 sites of membrane-proximal mutations are part of an O-linked glycosylation cluster. Mutation at these sites prevents O-glycosylation of CSF3R and increases receptor dimerization. This increased dimerization explains the ligand-independent activation of CSF3R membrane-proximal mutations. Cytokine receptor activation through loss of O-glycosylation represents a novel avenue of aberrant signaling. Finally, the combination of the CSF3R membrane proximal and truncation mutations, as has been reported in some patients, leads to enhanced cellular transformation when compared with either mutation alone, underscoring their distinct mechanisms of action.
Jeffrey W. Tyner - One of the best experts on this subject based on the ideXlab platform.
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CML: implications for diagnosis and treatment
2016Co-Authors: Jason Gotlib, Julia E Maxson, Tracy I. George, Jeffrey W. TynerAbstract:new genetics of Chronic Neutrophilic Leukemia and atypica
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durable disease control with mek inhibition in a patient with nras mutated atypical Chronic myeloid Leukemia
Cureus, 2015Co-Authors: Vishesh Khanna, Jeffrey W. Tyner, Scott T Pierce, Kimhien T Dao, Cristina E Tognon, David E Hunt, Brian Junio, Brian J DrukerAbstract:Atypical Chronic myeloid Leukemia (aCML) and Chronic Neutrophilic Leukemia (CNL) are rare hematologic neoplasms characterized by leukocytosis and a hypercellular bone marrow. Although recurrent mutations in the colony-stimulating factor 3 receptor (CSF3R) are frequently observed in patients with (CNL), the mutational landscape in (aCML) is less well-defined. In this report, we describe an 81-year-old male who was diagnosed with aCML. He presented with leukocytosis and anemia but no significant clinical symptoms. Standard laboratory studies revealed the absence of the Philadelphia chromosome. Massively parallel sequencing demonstrated no mutations in CSF3R, but the presence of a heterozygous NRAS-G12D variant (47% allele frequency). The patient was started on treatment with trametinib, an MEK1/2 inhibitor with Food and Drug Administration approval for malignant melanoma. Therapy with trametinib resulted in exceptional improvements in his blood counts and continued disease control with 14 months of follow-up. This case highlights the need for clinical trials evaluating the safety and efficacy of MEK1/2 as a therapeutic target for the treatment of patients with NRAS-mutated aCML/CNL.
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ligand independence of the t618i mutation in the colony stimulating factor 3 receptor csf3r protein results from loss of o linked glycosylation and increased receptor dimerization
Journal of Biological Chemistry, 2014Co-Authors: Julia E Maxson, Brian J Druker, Samuel B Luty, Jason D Macmaniman, Melissa L Abel, Jeffrey W. TynerAbstract:Mutations in the CSF3 granulocyte colony-stimulating factor receptor CSF3R have recently been found in a large percentage of patients with Chronic Neutrophilic Leukemia and, more rarely, in other types of Leukemia. These CSF3R mutations fall into two distinct categories: membrane-proximal mutations and truncation mutations. Although both classes of mutation have exhibited the capacity for cellular transformation, several aspects of this transformation, including the kinetics, the requirement for ligand, and the dysregulation of downstream signaling pathways, have all been shown to be discrepant between the mutation types, suggesting distinct mechanisms of activation. CSF3R truncation mutations induce overexpression and ligand hypersensitivity of the receptor, likely because of the removal of motifs necessary for endocytosis and degradation. In contrast, little is known about the mechanism of activation of membrane-proximal mutations, which are much more commonly observed in Chronic Neutrophilic Leukemia. In contrast with CSF3R truncation mutations, membrane-proximal mutations do not exhibit overexpression and are capable of signaling in the absence of ligand. We show that the Thr-615 and Thr-618 sites of membrane-proximal mutations are part of an O-linked glycosylation cluster. Mutation at these sites prevents O-glycosylation of CSF3R and increases receptor dimerization. This increased dimerization explains the ligand-independent activation of CSF3R membrane-proximal mutations. Cytokine receptor activation through loss of O-glycosylation represents a novel avenue of aberrant signaling. Finally, the combination of the CSF3R membrane proximal and truncation mutations, as has been reported in some patients, leads to enhanced cellular transformation when compared with either mutation alone, underscoring their distinct mechanisms of action.
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significant clinical response to jak1 2 inhibition in a patient with csf3r t618i positive atypical Chronic myeloid Leukemia
Leukemia research reports, 2014Co-Authors: Kimhien Dao, Julia E Maxson, Brian J Druker, Magdolna B Solti, Elliott F Winton, Richard D Press, Jeffrey W. TynerAbstract:Mutations in CSF3R (colony-stimulating factor 3 receptor) are frequent oncogenic drivers in Chronic Neutrophilic Leukemia (CNL) and atypical Chronic myeloid Leukemia (aCML). Here we describe a 75 year old man who was diagnosed with CSF3R-T618I-positive atypical CML. He presented with leukocytosis, anemia, and thrombocytopenia and developed massive splenomegaly and severe constitutional symptoms. Hydroxyurea was given over a 6 month period but failed to provide any measureable clinical benefit. Eventually, he was treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. This case highlights the need for a clinical trial to interrogate JAK1/2 as a potential molecular target in CNL and aCML in patients with or without CSF3R mutation. A clinical trial evaluating the safety and efficacy of ruxolitinib for this patient population is registered at ClinicalTrials.gov (NCT02092324).
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the csf3r t618i mutation causes a lethal Neutrophilic neoplasia in mice that is responsive to therapeutic jak inhibition
Blood, 2013Co-Authors: Angela G Fleischman, Julia E Maxson, Brian J Druker, Anupriya Agarwal, Samuel B Luty, Jason D Macmaniman, Melissa L Abel, Lacey R Royer, Marc M Loriaux, Jeffrey W. TynerAbstract:We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of Chronic Neutrophilic Leukemia (CNL) and atypical (BCR-ABL–negative) Chronic myeloid Leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I–expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration of the spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of Neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.
A Tefferi - One of the best experts on this subject based on the ideXlab platform.
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An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms
Leukemia, 2014Co-Authors: A Tefferi, A.m. Vannucchi, J Thiele, T BarbuiAbstract:Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the Chronic myeloid Leukemia-associated BCR-ABL1 . No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL -unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin ( CALR ) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2 , MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with Chronic Neutrophilic Leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively.
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Chronic Neutrophilic Leukemia with concurrent csf3r and setbp1 mutations single colony clonality studies in vitro sensitivity to jak inhibitors and lack of treatment response to ruxolitinib
Leukemia, 2014Co-Authors: Terra L Lasho, Alice S Mims, Michelle A Elliott, Christy Finke, Animesh Pardanani, A TefferiAbstract:Chronic Neutrophilic Leukemia with concurrent CSF3R and SETBP1 mutations: single colony clonality studies, in vitro sensitivity to JAK inhibitors and lack of treatment response to ruxolitinib
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Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms
Leukemia, 2008Co-Authors: A Tefferi, J W VardimanAbstract:The 2001 World Health Organization (WHO) treatise on the classification of hematopoietic tumors lists Chronic myeloproliferative diseases (CMPDs) as a subdivision of myeloid neoplasms that includes the four classic myeloproliferative disorders (MPDs)—Chronic myelogenous Leukemia, polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)—as well as Chronic Neutrophilic Leukemia (CNL), Chronic eosinophilic Leukemia/hypereosinophilic syndrome (CEL/HES) and ‘CMPD, unclassifiable’. In the upcoming 4th edition of the WHO document, due out in 2008, the term ‘CMPDs’ is replaced by ‘myeloproliferative neoplasms (MPNs)’, and the MPN category now includes mast cell disease (MCD), in addition to the other subcategories mentioned above. At the same time, however, myeloid neoplasms with molecularly characterized clonal eosinophilia, previously classified under CEL/HES, are now removed from the MPN section and assembled into a new category of their own. The WHO diagnostic criteria for both the classic BCR–ABL -negative MPDs (that is PV, ET and PMF) and CEL/HES have also been revised, in the 2008 edition, by incorporating new information on their molecular pathogenesis. The current review highlights these changes and also provides diagnostic algorithms that are tailored to routine clinical practice.
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SPOTLIGHT REVIEW Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms
2007Co-Authors: A Tefferi, J W VardimanAbstract:The 2001 World Health Organization (WHO) treatise on the classification of hematopoietic tumors lists Chronic myelopro-liferative diseases (CMPDs) as a subdivision of myeloid neoplasms that includes the four classic myeloproliferative disorders (MPDs)FChronic myelogenous Leukemia, polycythe-mia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)Fas well as Chronic Neutrophilic Leukemia (CNL), Chronic eosinophilic Leukemia/hypereosinophilic syn-drome (CEL/HES) and ‘CMPD, unclassifiable’. In the upcoming 4th edition of the WHO document, due out in 2008, the term ‘CMPDs ’ is replaced by ‘myeloproliferative neoplasms (MPNs)’, and the MPN category now includes mast cell disease (MCD), in addition to the other subcategories mentioned above. At the same time, however, myeloid neoplasms with molecularly characterized clonal eosinophilia, previously classified under CEL/HES, are now removed from the MPN section and assem-bled into a new category of their own. The WHO diagnostic criteria for both the classic BCR–ABL-negative MPDs (that is PV, ET and PMF) and CEL/HES have also been revised, in the 2008 edition, by incorporating new information on their molecular pathogenesis. The current review highlights these changes and also provides diagnostic algorithms that are tailored to routine clinical practice
Kenneth D Greis - One of the best experts on this subject based on the ideXlab platform.
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time resolved quantitative phospho tyrosine analysis reveals bruton s tyrosine kinase mediated signaling downstream of the mutated granulocyte colony stimulating factor receptors
Leukemia, 2019Co-Authors: Pankaj Dwivedi, David E Muench, Michael W Wagner, Mohammad Azam, Leighton H Grimes, Kenneth D GreisAbstract:Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with Chronic Neutrophilic Leukemia (CNL) and acute myeloid Leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we used a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical Stat3, Stat5, and Mapk phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (3–5-fold lower IC50) for ibrutinib-based chemical inhibition of Btk. Primary murine progenitor cells from G-CSFR-Q741x knock-in mice validated activation of Btk by the mutant receptor and retrovirally transduced human CD34+ umbilical cord blood cells expressing mutant receptors displayed enhanced sensitivity to Ibrutinib. A significantly lower clonogenic potential was displayed by both murine and human primary cells expressing mutated receptors upon ibrutinib treatment. Finally, a dramatic synergy was observed between ibrutinib and ruxolinitib at lower dose of the individual drug. Altogether, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid Leukemia bearing CSF3R mutations. Phospho-tyrosine data are available via ProteomeXchange with identifier PXD009662.
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granulocyte colony stimulating factor receptor signaling in severe congenital neutropenia Chronic Neutrophilic Leukemia and related malignancies
Experimental Hematology, 2017Co-Authors: Pankaj Dwivedi, Kenneth D GreisAbstract:Granulocyte colony-stimulating factor is a hematopoietic cytokine that stimulates neutrophil production and hematopoietic stem cell mobilization by initiating the dimerization of homodimeric granulocyte colony-stimulating factor receptor. Different mutations of CSF3R have been linked to a unique spectrum of myeloid disorders and related malignancies. Myeloid disorders caused by the CSF3R mutations include severe congenital neutropenia, Chronic Neutrophilic Leukemia, and atypical Chronic myeloid Leukemia. In this review, we provide an analysis of granulocyte colony-stimulating factor receptor, various mutations, and their roles in the severe congenital neutropenia, Chronic Neutrophilic Leukemia, and malignant transformation, as well as the clinical implications and some perspective on approaches that could expand our knowledge with respect to the normal signaling mechanisms and those associated with mutations in the receptor.
Kimhien Dao - One of the best experts on this subject based on the ideXlab platform.
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efficacy of ruxolitinib in patients with Chronic Neutrophilic Leukemia and atypical Chronic myeloid Leukemia
Journal of Clinical Oncology, 2020Co-Authors: Kimhien Dao, Jason Gotlib, M Deininger, Jorge E Cortes, Robert H Collins, E F Winton, Dana R Parker, Hyunjung Lee, Anna Reister Schultz, Samantha Savage L StevensAbstract:PURPOSEColony-stimulating factor-3 receptor (CSF3R)-T618I is a recurrent activating mutation in Chronic Neutrophilic Leukemia (CNL) and to a lesser extent in atypical Chronic myeloid Leukemia (aCML...
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genomic landscape of Neutrophilic Leukemias of ambiguous diagnosis
Blood, 2019Co-Authors: Haijiao Zhang, Kimhien Dao, Christopher A Eide, Daniel Bottomly, Beth Wilmot, Emily A Stevens, Vishesh Khanna, Angela Rofelty, Samantha L Savage, Anna Reister SchultzAbstract:Chronic Neutrophilic Leukemia (CNL), atypical Chronic myeloid Leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.
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significant clinical response to jak1 2 inhibition in a patient with csf3r t618i positive atypical Chronic myeloid Leukemia
Leukemia research reports, 2014Co-Authors: Kimhien Dao, Julia E Maxson, Brian J Druker, Magdolna B Solti, Elliott F Winton, Richard D Press, Jeffrey W. TynerAbstract:Mutations in CSF3R (colony-stimulating factor 3 receptor) are frequent oncogenic drivers in Chronic Neutrophilic Leukemia (CNL) and atypical Chronic myeloid Leukemia (aCML). Here we describe a 75 year old man who was diagnosed with CSF3R-T618I-positive atypical CML. He presented with leukocytosis, anemia, and thrombocytopenia and developed massive splenomegaly and severe constitutional symptoms. Hydroxyurea was given over a 6 month period but failed to provide any measureable clinical benefit. Eventually, he was treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. This case highlights the need for a clinical trial to interrogate JAK1/2 as a potential molecular target in CNL and aCML in patients with or without CSF3R mutation. A clinical trial evaluating the safety and efficacy of ruxolitinib for this patient population is registered at ClinicalTrials.gov (NCT02092324).