Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired mutations in the intracellular part of CSF3R (colony stimulating factor 3 receptor, granulocyte) have been detected with a frequency of more than 30% in severe congenital neutropenia (CN) patients. CN is a preleukemic syndrome with a risk of approximately 20% to develop leukemia. More than 80% of CN patients who develop acute myeloid leukemia or myelodysplastic syndrome reveal CSF3R mutations, suggesting that they are involved in leukemogenesis. Using deep-sequencing technology, we were able to analyze large cohorts of CN patients for the entire CSF3R sequence as well as to identify cell clones carrying mutations in the intracellular part of CSF3R with very high sensitivity. Acquisition of CSF3R mutations is a CN-specific phenomenon and is associated with inherited mutations causing CN or cyclic neutropenia, such as ELANE mutations. In the group of CN patients negative for known germ-line mutations, biallelic CSF3R mutations were identified. In addition, CSF3R mutant clones are highly dynamic and may disappear and reappear during continuous granulocyte colony-stimulating factor (G-CSF) therapy. The time between the first detection of CSF3R mutations and overt leukemia is highly variable.
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PMID:Role of CSF3R mutations in the pathomechanism of congenital neutropenia and secondary acute myeloid leukemia. 2727 Apr 96

Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.
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PMID:Transcription Factor GFI1B in Health and Disease. 2840 Oct 61

Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended.
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PMID:Severe congenital neutropenias. 2859 97

Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.
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PMID:Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review. 2957 39

Inherited bone marrow failure syndromes are experiments of nature characterized by impaired hematopoiesis with cancer and leukemia predisposition. The mutations associated with inherited bone marrow failure syndromes affect fundamental cellular pathways, such as DNA repair, telomere maintenance, or proteostasis. How these disturbed pathways fail to produce sufficient blood cells and lead to leukemogenesis are not understood. The rarity of inherited cytopenias, the paucity of affected primary human hematopoietic cells, and the sometime inadequacy of murine or induced pluripotential stem cell models mean it is difficult to acquire a greater understanding of them. Zebrafish offer a model organism to study gene functions. As vertebrates, zebrafish share with humans many orthologous genes involved in blood disorders. As a model organism, zebrafish provide advantages that include rapid development of transparent embryos, high fecundity (providing large numbers of mutant and normal siblings), and a large collection of mutant and transgenic lines useful for investigating the blood system and other tissues during development. Importantly, recent advances in genomic editing in zebrafish can speedily validate the new genes or novel variants discovered in clinical investigation as causes for marrow failure. Here we review zebrafish as a model organism that phenocopies Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, and severe congenital neutropenia. Two important insights, provided by modeling inherited cytopenias in zebrafish, widen understanding of ribosome biogenesis and TP53 in mediating marrow failure and non-hematologic defects. They suggest that TP53-independent pathways contribute to marrow failure. In addition, zebrafish provide an attractive model organism for drug development.
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PMID:Peering through zebrafish to understand inherited bone marrow failure syndromes. 3057 10

Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30-40%. The majority of SCN cases are due to a germline ELANE mutation. Acquired mutations in CSF3R occur in >70% sMDS/sAML associated with SCN. Hypotheses underlying our model are: an ELANE mutation causes SCN; CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells with CSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage. Applying population genetics theory, we propose a novel two-phase model of disease development from SCN to sMDS. In Phase 1, hematopoietic tissues expand and produce tens to hundreds of stem cells with the CSF3R truncation mutation. Phase 2 occurs postnatally through adult stages with bone marrow production of granulocyte precursors and positive selection of mutants due to chronic G-CSF therapy to reverse the severe neutropenia. We predict the existence of the pool of cells with the mutated truncated receptor before G-CSF treatment begins. The model does not require increase in mutation rate under G-CSF treatment and agrees with age distribution of sMDS onset and clinical sequencing data.
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PMID:Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia. 3061 12

High frequency of acquired CSF3R (colony stimulating factor 3 receptor, granulocyte) mutations has been described in patients with severe congenital neutropenia (CN) at pre-leukemia stage and overt acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Here, we report the establishment of an ultra-sensitive deep sequencing of a CSF3R segment encoding the intracellular "critical region" of the G-CSFR known to be mutated in CN-MDS/AML patients. Using this method, we achieved a mutant allele frequency (MAF) detection rate of 0.01%. We detected CSF3R mutations in CN patients with different genetic backgrounds, but not in patients with other types of bone marrow failure syndromes chronically treated with G-CSF (e.g., Shwachman-Diamond Syndrome). Comparison of CSF3R deep sequencing results of DNA and cDNA from the bone marrow and peripheral blood cells revealed the highest sensitivity of cDNA from the peripheral blood polymorphonuclear neutrophils. This approach enables the identification of low-frequency CSF3R mutant clones, increases sensitivity, and earlier detection of CSF3R mutations acquired during the course of leukemogenic evolution of pre-leukemia HSCs of CN patients. We suggest application of sequencing of the entire CSF3R gene at diagnosis to identify patients with inherited lost-of-function CSF3R mutations and annual ultra-deep sequencing of the critical region of CSF3R to monitor acquisition of CSF3R mutations.
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PMID:Ultra-Sensitive CSF3R Deep Sequencing in Patients With Severe Congenital Neutropenia. 3089 Oct 28

Somatic RUNX1 mutations are found in approximately 10% of patients with de novo acute myeloid leukemia (AML), but are more common in secondary forms of myelodysplastic syndrome (MDS) or AML. Particularly, this applies to MDS/AML developing from certain types of leukemia-prone inherited bone marrow failure syndromes. How these RUNX1 mutations contribute to the pathobiology of secondary MDS/AML is still unknown. This mini-review focusses on the role of RUNX1 mutations as the most common secondary leukemogenic hit in MDS/AML evolving from severe congenital neutropenia (SCN).
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PMID:RUNX1 Mutations in the Leukemic Progression of Severe Congenital Neutropenia. 3204 95

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes-such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias-also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.
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PMID:Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers. 3257 4

Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.
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PMID:Cooperating, congenital neutropenia-associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs. 3282 71


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