The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Linda J. Bendall - One of the best experts on this subject based on the ideXlab platform.
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Role of WNT signaling in normal and Malignant Hematopoiesis.
Histology and histopathology, 2006Co-Authors: Naveed I. Khan, Linda J. BendallAbstract:Summary. The WNT pathway is a powerful signaling pathway that plays a crucial role in cell fate determination, survival, proliferation and movement in variety of tissues. Abnormalities in the WNT signaling pathway have been implicated in a number of diseases, most notably cancer. Recent exciting evidence suggests that WNT signaling also plays an important role in hematopoietic stem cell self-renewal and progenitor development. In this review we discuss current state of knowledge on WNT signaling in Hematopoiesis and extend our focus on aberrant WNT signaling in hematological malignancies.
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sdf 1 and cxcr4 in normal and Malignant Hematopoiesis
Histology and Histopathology, 2004Co-Authors: Julius Juarez, Linda J. BendallAbstract:Over recent years it has become apparent that the chemokine SDF-1 and its receptor CXCR4 play pivotal roles in normal Hematopoiesis. They are essential for the normal ontogeny of Hematopoiesis during embryogenesis and continue to play a key role in retaining hematopoietic progenitors within the bone marrow microenvironment in the adult. As a result of this role disruption of SDF-1/CXCR4 interactions results in mobilization of hematopoietic progenitors and standard mobilization protocols disrupt this axis. Similarly SDF-1/CXCR4 interactions are required for homing and engraftment of hematopoietic stem cells during transplantation. SDF-1 regulates the localisation of leukemic cells and like their normal counterparts most leukemic cells respond to SDF-1 with increased adhesion, survival and proliferation. However in some instances leukemic cell responses to SDF-1 can be disregulated, the impact of which on the progression of disease in not known. In this review we discuss the pleiotropic roles of SDF-1/CXCR4 interactions in human hematopoietic stem cell ontogeny, bone marrow homing and engraftment, mobilization and how these interactions impact on Malignant Hematopoiesis.
Harvey F. Lodish - One of the best experts on this subject based on the ideXlab platform.
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emerging mechanisms of long noncoding rna function during normal and Malignant Hematopoiesis
Blood, 2017Co-Authors: Juan R Alvarezdominguez, Harvey F. LodishAbstract:Long noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to Malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.
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Long noncoding RNAs during normal and Malignant Hematopoiesis
International Journal of Hematology, 2014Co-Authors: Juan R. Alvarez-dominguez, Austin A. Gromatzky, Harvey F. LodishAbstract:Long noncoding RNAs (lncRNAs) are increasingly recognized to contribute to cellular development via diverse mechanisms during both health and disease. Here, we highlight recent progress on the study of lncRNAs that function in the development of blood cells. We emphasize lncRNAs that regulate blood cell fates through epigenetic control of gene expression, an emerging theme among functional lncRNAs. Many of these noncoding genes and their targets become dysregulated during Malignant Hematopoiesis, directly implicating lncRNAs in blood cancers such as leukemia. In a few cases, dysregulation of an lncRNA alone leads to Malignant Hematopoiesis in a mouse model. Thus, lncRNAs may be not only useful as markers for the diagnosis and prognosis of cancers of the blood, but also as potential targets for novel therapies.
Virginie Chesnais - One of the best experts on this subject based on the ideXlab platform.
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sustained leukemia free state and molecular response to sorafenib in a patient with chronic myelomonocytic leukemia in transformation driven by homozygous flt3 itd Malignant Hematopoiesis
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie ChesnaisAbstract:Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie Chesnais, Isabelle Radford-Weiss, Valerie Bardet, Patrick Mayeux, Jerome Tamburini, Michaela Fontenay, Didier Bouscary
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targeted therapy in cmml complete molecular response to sorafenib in a patient with a flt3 itd Malignant Hematopoiesis
Blood, 2012Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Lise Willems, Virginie Chesnais, Pascaline Boudourouquette, Isabelle Radfordweiss, Valerie Bardet, Patrick MayeuxAbstract:Abstract Abstract 4786 Background Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic stem cell disorder whom biology remains unclear.CMML is associated with many different somatic mutations in genes involved in key cellular processes including signaling (N/K-Ras, CBL, JAK2); differentiation (RUNX1, NPM1, CEBPa); epigenetic regulation (TET2, ASXL1, IDH1/2, EZH2, DNMT3A); and RNA splicing (SRSF2, U2AF1, SF3B1 and ZRSR2). FLT3 mutations are very rare but provide the rationale for FLT3 tyrosine kinase inhibitor use to treat this disease. We report the case of a 60-years-old patient diagnosed with a hepatocarcinoma metastasis which legitimized the introduction of anti-angiogenic therapy using the VEGF-R2 inhibitor, sorafenib. The patient was addressed to the hematology department with a myeloproliferative-like CMML in transformation. We show here that the molecular analyses of this hematological disorders allow us to use sorafenib as a targeted therapy to inhibit the consequences of a FLT3-ITD mutation. Methods Cytogenetic analysis and genome wide array-based comparative genomic hybridization (aCGH) were performed at diagnosis. The reference standard used for aCGH was matched genomic constitutional DNA (CD3+ T cells sorted from a blood sample). Serum samples collected from the patient before or under treatment with sorafenib were assessed for their plasma inhibitory activity by western blotting analyses of signaling molecules downstream the FLT3-ITD mutation. Genomic DNA samples extracted from BMMCs and peripheral blood (PB) cells at diagnosis were screened for mutations in 18 classical genes. To monitor the FLT3-ITD mutation, the exon 15 of FLT3 was amplified by a specific PCR using a 6FAM-labeled forward primer. Results The patient developed hyperleucocytosis (48.2 G/L) with neutrophilia (30.4 G/L), monocytosis (11.6 G/L) and basophilia (0.5 G/L) in January 2011. The BM was hypercellular with granulocytic and monocytic proliferation, dysgranulopoiesis and dysmegacaryopoiesis. Blast cells plus promonocytes accounted for 30% of the nucleated BM cells, leading to a diagnosis of AML secondary to CMML in the WHO classification BM karyotype identified no clonal abnormalities and aCGH analysis of BMMCs produced normal findings. BM and PB cells were screened for mutations in 18 CMML-associated genes. Only two abnormalities were identified: a 27 base pair (bp) insertion FLT3-ITD mutation (exon 15) detected in BM cells with near complete disappearance of the wild type (WT) FLT3 allele (FLT3-ITD/FLT3-WT ratio at 9.62) and a classical heterozygous mutation (dupG) was found in the exon 12 of ASXL1. ASXL1 and FLT3-ITD mutations were not detected in purified CD3+ T lymphocytes. Five months after sorafenib introduction, PB was strictly normal and BM examination demonstrated normal richness, blast cells and promonocytes accounting for 2% of the nucleated BM cells but persistent moderate dysgranulopoiesis and dysmegakaryopoiesis, indicative of complete remission. At this time, the FLT3-ITD/FLT3-WT ratio was 1.66 and 0.58 in the BM and PB, respectively. In January 2012, the WBC profile was still normal and a BM smear only showed moderate dysgranulopoiesis. On the molecular side, FLT3-ITD mutation was undetectable, indicative of complete molecular response. But ASXL1 mutation was evident at all time points. The serum of the patient, obtained before and under sorafenib was tested on cell line harboring FLT3-ITD mutation. Constitutive FLT3 Y591, Akt S473, STAT5 Y694 and ERK1/2 T202/Y204 phosphorylations were fully inhibited in the presence of the serum extracted under sorafenib treatment. Conclusion Our patient clearly had a myeloproliferative-CMML driven by an homozygous FLT3-ITD mutation. This is the first report of such a CMML patient achieving sustained CR and CMR after treatment with an FLT3-ITD tyrosine kinase inhibitor. In this case, the ASXL1 mutation remained detectable upon sorafenib treatment after the suppression of FLT3-ITD-driven Malignant Hematopoiesis, suggesting that it arose from a FLT3-WT subclone that contributed to the CMML phenotype with some dysplastic feature. In conclusion, we propose that mutations in the FLT3 gene should be examinated in all CMML cases, even their low frequency because FLT3 TKI may induce dramatic and sustained responses without significant toxicity and eventually allow for allogenic transplantation. Disclosures: No relevant conflicts of interest to declare.
Lise Willems - One of the best experts on this subject based on the ideXlab platform.
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sustained leukemia free state and molecular response to sorafenib in a patient with chronic myelomonocytic leukemia in transformation driven by homozygous flt3 itd Malignant Hematopoiesis
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie ChesnaisAbstract:Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie Chesnais, Isabelle Radford-Weiss, Valerie Bardet, Patrick Mayeux, Jerome Tamburini, Michaela Fontenay, Didier Bouscary
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targeted therapy in cmml complete molecular response to sorafenib in a patient with a flt3 itd Malignant Hematopoiesis
Blood, 2012Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Lise Willems, Virginie Chesnais, Pascaline Boudourouquette, Isabelle Radfordweiss, Valerie Bardet, Patrick MayeuxAbstract:Abstract Abstract 4786 Background Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic stem cell disorder whom biology remains unclear.CMML is associated with many different somatic mutations in genes involved in key cellular processes including signaling (N/K-Ras, CBL, JAK2); differentiation (RUNX1, NPM1, CEBPa); epigenetic regulation (TET2, ASXL1, IDH1/2, EZH2, DNMT3A); and RNA splicing (SRSF2, U2AF1, SF3B1 and ZRSR2). FLT3 mutations are very rare but provide the rationale for FLT3 tyrosine kinase inhibitor use to treat this disease. We report the case of a 60-years-old patient diagnosed with a hepatocarcinoma metastasis which legitimized the introduction of anti-angiogenic therapy using the VEGF-R2 inhibitor, sorafenib. The patient was addressed to the hematology department with a myeloproliferative-like CMML in transformation. We show here that the molecular analyses of this hematological disorders allow us to use sorafenib as a targeted therapy to inhibit the consequences of a FLT3-ITD mutation. Methods Cytogenetic analysis and genome wide array-based comparative genomic hybridization (aCGH) were performed at diagnosis. The reference standard used for aCGH was matched genomic constitutional DNA (CD3+ T cells sorted from a blood sample). Serum samples collected from the patient before or under treatment with sorafenib were assessed for their plasma inhibitory activity by western blotting analyses of signaling molecules downstream the FLT3-ITD mutation. Genomic DNA samples extracted from BMMCs and peripheral blood (PB) cells at diagnosis were screened for mutations in 18 classical genes. To monitor the FLT3-ITD mutation, the exon 15 of FLT3 was amplified by a specific PCR using a 6FAM-labeled forward primer. Results The patient developed hyperleucocytosis (48.2 G/L) with neutrophilia (30.4 G/L), monocytosis (11.6 G/L) and basophilia (0.5 G/L) in January 2011. The BM was hypercellular with granulocytic and monocytic proliferation, dysgranulopoiesis and dysmegacaryopoiesis. Blast cells plus promonocytes accounted for 30% of the nucleated BM cells, leading to a diagnosis of AML secondary to CMML in the WHO classification BM karyotype identified no clonal abnormalities and aCGH analysis of BMMCs produced normal findings. BM and PB cells were screened for mutations in 18 CMML-associated genes. Only two abnormalities were identified: a 27 base pair (bp) insertion FLT3-ITD mutation (exon 15) detected in BM cells with near complete disappearance of the wild type (WT) FLT3 allele (FLT3-ITD/FLT3-WT ratio at 9.62) and a classical heterozygous mutation (dupG) was found in the exon 12 of ASXL1. ASXL1 and FLT3-ITD mutations were not detected in purified CD3+ T lymphocytes. Five months after sorafenib introduction, PB was strictly normal and BM examination demonstrated normal richness, blast cells and promonocytes accounting for 2% of the nucleated BM cells but persistent moderate dysgranulopoiesis and dysmegakaryopoiesis, indicative of complete remission. At this time, the FLT3-ITD/FLT3-WT ratio was 1.66 and 0.58 in the BM and PB, respectively. In January 2012, the WBC profile was still normal and a BM smear only showed moderate dysgranulopoiesis. On the molecular side, FLT3-ITD mutation was undetectable, indicative of complete molecular response. But ASXL1 mutation was evident at all time points. The serum of the patient, obtained before and under sorafenib was tested on cell line harboring FLT3-ITD mutation. Constitutive FLT3 Y591, Akt S473, STAT5 Y694 and ERK1/2 T202/Y204 phosphorylations were fully inhibited in the presence of the serum extracted under sorafenib treatment. Conclusion Our patient clearly had a myeloproliferative-CMML driven by an homozygous FLT3-ITD mutation. This is the first report of such a CMML patient achieving sustained CR and CMR after treatment with an FLT3-ITD tyrosine kinase inhibitor. In this case, the ASXL1 mutation remained detectable upon sorafenib treatment after the suppression of FLT3-ITD-driven Malignant Hematopoiesis, suggesting that it arose from a FLT3-WT subclone that contributed to the CMML phenotype with some dysplastic feature. In conclusion, we propose that mutations in the FLT3 gene should be examinated in all CMML cases, even their low frequency because FLT3 TKI may induce dramatic and sustained responses without significant toxicity and eventually allow for allogenic transplantation. Disclosures: No relevant conflicts of interest to declare.
Sophie Kaltenbach - One of the best experts on this subject based on the ideXlab platform.
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sustained leukemia free state and molecular response to sorafenib in a patient with chronic myelomonocytic leukemia in transformation driven by homozygous flt3 itd Malignant Hematopoiesis
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie ChesnaisAbstract:Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie Chesnais, Isabelle Radford-Weiss, Valerie Bardet, Patrick Mayeux, Jerome Tamburini, Michaela Fontenay, Didier Bouscary
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targeted therapy in cmml complete molecular response to sorafenib in a patient with a flt3 itd Malignant Hematopoiesis
Blood, 2012Co-Authors: Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Lise Willems, Virginie Chesnais, Pascaline Boudourouquette, Isabelle Radfordweiss, Valerie Bardet, Patrick MayeuxAbstract:Abstract Abstract 4786 Background Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic stem cell disorder whom biology remains unclear.CMML is associated with many different somatic mutations in genes involved in key cellular processes including signaling (N/K-Ras, CBL, JAK2); differentiation (RUNX1, NPM1, CEBPa); epigenetic regulation (TET2, ASXL1, IDH1/2, EZH2, DNMT3A); and RNA splicing (SRSF2, U2AF1, SF3B1 and ZRSR2). FLT3 mutations are very rare but provide the rationale for FLT3 tyrosine kinase inhibitor use to treat this disease. We report the case of a 60-years-old patient diagnosed with a hepatocarcinoma metastasis which legitimized the introduction of anti-angiogenic therapy using the VEGF-R2 inhibitor, sorafenib. The patient was addressed to the hematology department with a myeloproliferative-like CMML in transformation. We show here that the molecular analyses of this hematological disorders allow us to use sorafenib as a targeted therapy to inhibit the consequences of a FLT3-ITD mutation. Methods Cytogenetic analysis and genome wide array-based comparative genomic hybridization (aCGH) were performed at diagnosis. The reference standard used for aCGH was matched genomic constitutional DNA (CD3+ T cells sorted from a blood sample). Serum samples collected from the patient before or under treatment with sorafenib were assessed for their plasma inhibitory activity by western blotting analyses of signaling molecules downstream the FLT3-ITD mutation. Genomic DNA samples extracted from BMMCs and peripheral blood (PB) cells at diagnosis were screened for mutations in 18 classical genes. To monitor the FLT3-ITD mutation, the exon 15 of FLT3 was amplified by a specific PCR using a 6FAM-labeled forward primer. Results The patient developed hyperleucocytosis (48.2 G/L) with neutrophilia (30.4 G/L), monocytosis (11.6 G/L) and basophilia (0.5 G/L) in January 2011. The BM was hypercellular with granulocytic and monocytic proliferation, dysgranulopoiesis and dysmegacaryopoiesis. Blast cells plus promonocytes accounted for 30% of the nucleated BM cells, leading to a diagnosis of AML secondary to CMML in the WHO classification BM karyotype identified no clonal abnormalities and aCGH analysis of BMMCs produced normal findings. BM and PB cells were screened for mutations in 18 CMML-associated genes. Only two abnormalities were identified: a 27 base pair (bp) insertion FLT3-ITD mutation (exon 15) detected in BM cells with near complete disappearance of the wild type (WT) FLT3 allele (FLT3-ITD/FLT3-WT ratio at 9.62) and a classical heterozygous mutation (dupG) was found in the exon 12 of ASXL1. ASXL1 and FLT3-ITD mutations were not detected in purified CD3+ T lymphocytes. Five months after sorafenib introduction, PB was strictly normal and BM examination demonstrated normal richness, blast cells and promonocytes accounting for 2% of the nucleated BM cells but persistent moderate dysgranulopoiesis and dysmegakaryopoiesis, indicative of complete remission. At this time, the FLT3-ITD/FLT3-WT ratio was 1.66 and 0.58 in the BM and PB, respectively. In January 2012, the WBC profile was still normal and a BM smear only showed moderate dysgranulopoiesis. On the molecular side, FLT3-ITD mutation was undetectable, indicative of complete molecular response. But ASXL1 mutation was evident at all time points. The serum of the patient, obtained before and under sorafenib was tested on cell line harboring FLT3-ITD mutation. Constitutive FLT3 Y591, Akt S473, STAT5 Y694 and ERK1/2 T202/Y204 phosphorylations were fully inhibited in the presence of the serum extracted under sorafenib treatment. Conclusion Our patient clearly had a myeloproliferative-CMML driven by an homozygous FLT3-ITD mutation. This is the first report of such a CMML patient achieving sustained CR and CMR after treatment with an FLT3-ITD tyrosine kinase inhibitor. In this case, the ASXL1 mutation remained detectable upon sorafenib treatment after the suppression of FLT3-ITD-driven Malignant Hematopoiesis, suggesting that it arose from a FLT3-WT subclone that contributed to the CMML phenotype with some dysplastic feature. In conclusion, we propose that mutations in the FLT3 gene should be examinated in all CMML cases, even their low frequency because FLT3 TKI may induce dramatic and sustained responses without significant toxicity and eventually allow for allogenic transplantation. Disclosures: No relevant conflicts of interest to declare.