Ignite Creation Date:
2024-05-06 @ 2:20 PM
Last Modification Date:
2024-10-26 @ 1:29 PM
Study NCT ID:
NCT04288739
Status:
UNKNOWN
Last Update Posted:
2020-07-09
First Post:
2020-02-23
Brief Title:
Immunophenotyping and Xist Gene in AML
Sponsor:
Assiut University
Organization:
Assiut University
Study Overview
Official Title:
Relationship Between Immunophenotyping and X-inactive Specific Transcript Xist Gene in Acute Myeloid Leukemia
Status:
UNKNOWN
Status Verified Date:
2020-07
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Xist
Brief Summary:
Acute myeloid leukemia AML is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors blasts in the bone marrow and peripheral bloodSeveral studies have reported correlations of aberrantly expressed markers by flowcytometry with clinical outcome in AML X-inactive specific transcript RNA was one of the first long noncoding RNAs lncRNAs to be discovered in the early 1990s Xist RNA is the master regulator of XCI the epigenetic process that equalizes the dosage of X-linked genes between female XX and male XY mammals Yildirim et al 2013 deleted Xist in the blood compartment of mice and demonstrated that mutant females developed a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome mixed MPNMDS with 100 penetrance
Their study implies that human hematologic cancers may result from overdosage of X either from Xist loss on Xi or from duplication of Xa And they proposed that carcinogenesis is driven by a series of changes occurring in the HSC and further accumulated in mature hematopoietic cells These changes are initiated by loss of Xist which leads to progressive X reactivation which in turn induces a cascade of unfavorable genome-wide changes that include dysregulation of genes involved in DNA replication chromosome segregation cell-cycle checkpoints and hematopoiesis A failure of HSC maturation and loss of long-term HSC in the marrow progressively shift hematopoiesis to extramedullary sites resulting in extra medullary hematopoiesis EMH thereby causally linking the X chromosome to cancer in mice Thus they concluded that Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo
Indeed the emerging role of aberrant gene dosage in diseases whether of the X chromosome or for autosomes brings with it the possible application of drugs that impact on epigenetic regulators in potential therapeutic strategies
To date there are no published studies on human about Xist gene and its relationship with the immunophenotyping in AML patients So this will be the first study designed to explain its unexplored pathway in AML and detect its prognostic role and immunophenotypic association
Their study implies that human hematologic cancers may result from overdosage of X either from Xist loss on Xi or from duplication of Xa And they proposed that carcinogenesis is driven by a series of changes occurring in the HSC and further accumulated in mature hematopoietic cells These changes are initiated by loss of Xist which leads to progressive X reactivation which in turn induces a cascade of unfavorable genome-wide changes that include dysregulation of genes involved in DNA replication chromosome segregation cell-cycle checkpoints and hematopoiesis A failure of HSC maturation and loss of long-term HSC in the marrow progressively shift hematopoiesis to extramedullary sites resulting in extra medullary hematopoiesis EMH thereby causally linking the X chromosome to cancer in mice Thus they concluded that Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo
Indeed the emerging role of aberrant gene dosage in diseases whether of the X chromosome or for autosomes brings with it the possible application of drugs that impact on epigenetic regulators in potential therapeutic strategies
To date there are no published studies on human about Xist gene and its relationship with the immunophenotyping in AML patients So this will be the first study designed to explain its unexplored pathway in AML and detect its prognostic role and immunophenotypic association
Detailed Description:
Acute myeloid leukemia AML is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors blasts in the bone marrow and peripheral blood with high mortality and variable prognosis AML is the most common acute leukemia in adults accounting for 80 percent of cases in this group There are approximately 19520 new cases of AML in the United States US each year and 10670 deaths from AML In Egypt the incidence of AML was 096 for males and 114 for females according to the results of the National Population-Based Registry Program of Egypt 2008-2011 Diagnosis of AML based on morphological diagnosis with proliferation of blast cells 20 of marrow cells flow cytomtric immunophenotyping and cytogenetic abnormalities
Immunophenotyping via flow cytometry comprises an additional fast technique to predict outcome in AML although only few markers are yet established as prognostic factors in clinical routine diagnosis despite the fact that new and rapidly available markers are needed to improve the treatment decisions in AML patients This is even more since therapy in AML patients must be initiated immediately after diagnosis AML blasts express antigens found also on healthy immature myeloid cells including common differentiation CD markers CD13 CD33 and CD34 Other cells markers are expressed depending on the morphological subtype of AML and stage of differentiation block such as monocytic differentiation markers CD4 CD14 CD11b CD11c CD64 CD36 erythroid CD36 CD71 and megakaryocytic markers CD41a and CD61
Non-random chromosomal abnormalities eg deletions translocations are identified in approximately 52 of all adult primary AML patients and have long been recognized as the genetic events that cause and promote this disease Certain cytogenetic abnormalities including the t821q22q22 t1517q22q12 and inv16p131q22 are associated with longer remission and survival while alterations of chromosomes 5 7 complex karyotype described as 3 chromosomal abnormalities and 11q23 are associated with poor response to therapy and shorter overall survival
Several studies have reported correlations of aberrantly expressed markers with clinical outcome in AML For example CD7 and CD25 expression has been associated with poor prognosis in normal karyotype NK AML The IL3 receptor alfa CD123 is overexpressed in 45 of AML patients and this higher expression has also been associated with poor outcome and correlated with mutations in the fms-like tyrosine kinase receptor FLT3 gene A consistent antigenic profile with high CD33 expression has also been associated with AML with mutated nucleophosmin NPM1 Lo-Coco et al 2015 results suggest that the CD342512399ve leukemia-associated immunophenotypes LAIPs is strictly associated with FLT3-ITD positive cells This identification through multiparametric flow cytometry at diagnosis of an immunophenotypic fingerprint associated with these subclones is a novel and simplified tool with improved sensitivity to unravel these clones and allowing patient stratification and risk adapted treatment with potential impact on outcome of the disease
At present the etiological agent and pathogenesis of AML are not entirely clear only few AML cases can be accurately classified through traditional cellular morphological classification Thus it is very difficult to judge the disease condition and predict prognosis Improper expression of specific genes is a common finding in AML and may induce clinically relevant biological subsets Consequently identification of novel biomarkers which could predict outcome or guide treatment choice will make more contribution to the clinical management of AML
X chromosome aneuploidies have long been associated with human cancers but causality has not been established In mammals X chromosome inactivation XCI is triggered by X-inactive specific transcript Xist RNA to equalize gene expression between the sexes In humans one X chromosome is inactivated Xi in every female cell in order to achieve transcriptional balance An X-linked inactivation centre XIC is responsible for the initiation of X inactivation The exact size of the XIC is unclear but it includes the Xistgene at Xq132 This encodes a large non-coding RNA that is initially expressed on both X chromosomes before ceasing expression on the active X and becoming upregulated on the X that is to become inactivated The Xist RNA product coats the future Xi chromosome spreading out from the XIC
X-inactive specific transcript RNA was one of the first long noncoding RNAs lncRNAs to be discovered in the early 1990s a decade before the Human Genome Project HGP revealed that the large majority of our genome accounts for noncoding sequences Xist is a 19 kb spliced untranslated regulatory transcript that coats the X chromosome from which it is expressed in cis Xist RNA is the master regulator of XCI the epigenetic process that equalizes the dosage of X-linked genes between female XX and male XY mammals Deletion of the Xist gene results in skewed inactivation of the wild type X chromosome indicating that this locus is essential for gene silencing
The early transgenic studies also unveiled two key features of Xists function First the ability of Xist RNA to trigger gene silencing is strictly dependent on the developmental context Second Xist has different tasks such as cis-localization to the chromosome from which it is expressed and the ability to trigger gene silencing and these tasks are mediated by genetically independent domains of the RNA Moreover inappropriate silencing of human Xist results in qualitatively aberrant stem cells Whereas Xist has been investigated extensively in cell culture in vivo studies have been limited however none of these studies has been done in human
In some cases Xist RNA mislocalisation and sporadic Xi reactivation has been observed For example one study on an ovarian cancer cell line showed a disruption of Xist expression and potential reactivation of the Membrane Palmitoylated Protein-1 MPP1 p55 gene Previous study showed that the inactive X chromosome is genetically unstable in cancer as this study reporting an higher mutations rate on the inactive X compare to rest of the genome
Xist deletion in the blood compartment of mice demonstrated that mutant females developed a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome mixed MPNMDS with 100 penetrance Significant disease components include primary myelofibrosis leukemia histiocytic sarcoma and vasculitis They found that proliferative and dysplastic changes were present in all hematopoietic cell types Also Xist-deficient hematopoietic stem cells HSCs showed aberrant maturation and age-dependent loss of long-term HSCs
Their study implies that human hematologic cancers may result from overdosage of X either from Xist loss on Xi or from duplication of Xa And they proposed that carcinogenesis is driven by a series of changes occurring in the HSC and further accumulated in mature hematopoietic cells These changes are initiated by loss of Xist which leads to progressive X reactivation which in turn induces a cascade of unfavorable genome-wide changes that include dysregulation of genes involved in DNA replication chromosome segregation cell-cycle checkpoints and hematopoiesis A failure of HSC maturation and loss of long-term HSC in the marrow progressively shift hematopoiesis to extramedullary sites resulting in extra medullary hematopoiesis EMH thereby causally linking the X chromosome to cancer in mice Thus they concluded that Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo
Indeed the emerging role of aberrant gene dosage in diseases whether of the X chromosome or for autosomes brings with it the possible application of drugs that impact on epigenetic regulators in potential therapeutic strategies
To date there are no published studies on human about Xist gene and its relationship with the immunophenotyping in AML patients So this will be the first study designed to explain its unexplored pathway in AML and detect its prognostic role and immunophenotypic association
Immunophenotyping via flow cytometry comprises an additional fast technique to predict outcome in AML although only few markers are yet established as prognostic factors in clinical routine diagnosis despite the fact that new and rapidly available markers are needed to improve the treatment decisions in AML patients This is even more since therapy in AML patients must be initiated immediately after diagnosis AML blasts express antigens found also on healthy immature myeloid cells including common differentiation CD markers CD13 CD33 and CD34 Other cells markers are expressed depending on the morphological subtype of AML and stage of differentiation block such as monocytic differentiation markers CD4 CD14 CD11b CD11c CD64 CD36 erythroid CD36 CD71 and megakaryocytic markers CD41a and CD61
Non-random chromosomal abnormalities eg deletions translocations are identified in approximately 52 of all adult primary AML patients and have long been recognized as the genetic events that cause and promote this disease Certain cytogenetic abnormalities including the t821q22q22 t1517q22q12 and inv16p131q22 are associated with longer remission and survival while alterations of chromosomes 5 7 complex karyotype described as 3 chromosomal abnormalities and 11q23 are associated with poor response to therapy and shorter overall survival
Several studies have reported correlations of aberrantly expressed markers with clinical outcome in AML For example CD7 and CD25 expression has been associated with poor prognosis in normal karyotype NK AML The IL3 receptor alfa CD123 is overexpressed in 45 of AML patients and this higher expression has also been associated with poor outcome and correlated with mutations in the fms-like tyrosine kinase receptor FLT3 gene A consistent antigenic profile with high CD33 expression has also been associated with AML with mutated nucleophosmin NPM1 Lo-Coco et al 2015 results suggest that the CD342512399ve leukemia-associated immunophenotypes LAIPs is strictly associated with FLT3-ITD positive cells This identification through multiparametric flow cytometry at diagnosis of an immunophenotypic fingerprint associated with these subclones is a novel and simplified tool with improved sensitivity to unravel these clones and allowing patient stratification and risk adapted treatment with potential impact on outcome of the disease
At present the etiological agent and pathogenesis of AML are not entirely clear only few AML cases can be accurately classified through traditional cellular morphological classification Thus it is very difficult to judge the disease condition and predict prognosis Improper expression of specific genes is a common finding in AML and may induce clinically relevant biological subsets Consequently identification of novel biomarkers which could predict outcome or guide treatment choice will make more contribution to the clinical management of AML
X chromosome aneuploidies have long been associated with human cancers but causality has not been established In mammals X chromosome inactivation XCI is triggered by X-inactive specific transcript Xist RNA to equalize gene expression between the sexes In humans one X chromosome is inactivated Xi in every female cell in order to achieve transcriptional balance An X-linked inactivation centre XIC is responsible for the initiation of X inactivation The exact size of the XIC is unclear but it includes the Xistgene at Xq132 This encodes a large non-coding RNA that is initially expressed on both X chromosomes before ceasing expression on the active X and becoming upregulated on the X that is to become inactivated The Xist RNA product coats the future Xi chromosome spreading out from the XIC
X-inactive specific transcript RNA was one of the first long noncoding RNAs lncRNAs to be discovered in the early 1990s a decade before the Human Genome Project HGP revealed that the large majority of our genome accounts for noncoding sequences Xist is a 19 kb spliced untranslated regulatory transcript that coats the X chromosome from which it is expressed in cis Xist RNA is the master regulator of XCI the epigenetic process that equalizes the dosage of X-linked genes between female XX and male XY mammals Deletion of the Xist gene results in skewed inactivation of the wild type X chromosome indicating that this locus is essential for gene silencing
The early transgenic studies also unveiled two key features of Xists function First the ability of Xist RNA to trigger gene silencing is strictly dependent on the developmental context Second Xist has different tasks such as cis-localization to the chromosome from which it is expressed and the ability to trigger gene silencing and these tasks are mediated by genetically independent domains of the RNA Moreover inappropriate silencing of human Xist results in qualitatively aberrant stem cells Whereas Xist has been investigated extensively in cell culture in vivo studies have been limited however none of these studies has been done in human
In some cases Xist RNA mislocalisation and sporadic Xi reactivation has been observed For example one study on an ovarian cancer cell line showed a disruption of Xist expression and potential reactivation of the Membrane Palmitoylated Protein-1 MPP1 p55 gene Previous study showed that the inactive X chromosome is genetically unstable in cancer as this study reporting an higher mutations rate on the inactive X compare to rest of the genome
Xist deletion in the blood compartment of mice demonstrated that mutant females developed a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome mixed MPNMDS with 100 penetrance Significant disease components include primary myelofibrosis leukemia histiocytic sarcoma and vasculitis They found that proliferative and dysplastic changes were present in all hematopoietic cell types Also Xist-deficient hematopoietic stem cells HSCs showed aberrant maturation and age-dependent loss of long-term HSCs
Their study implies that human hematologic cancers may result from overdosage of X either from Xist loss on Xi or from duplication of Xa And they proposed that carcinogenesis is driven by a series of changes occurring in the HSC and further accumulated in mature hematopoietic cells These changes are initiated by loss of Xist which leads to progressive X reactivation which in turn induces a cascade of unfavorable genome-wide changes that include dysregulation of genes involved in DNA replication chromosome segregation cell-cycle checkpoints and hematopoiesis A failure of HSC maturation and loss of long-term HSC in the marrow progressively shift hematopoiesis to extramedullary sites resulting in extra medullary hematopoiesis EMH thereby causally linking the X chromosome to cancer in mice Thus they concluded that Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo
Indeed the emerging role of aberrant gene dosage in diseases whether of the X chromosome or for autosomes brings with it the possible application of drugs that impact on epigenetic regulators in potential therapeutic strategies
To date there are no published studies on human about Xist gene and its relationship with the immunophenotyping in AML patients So this will be the first study designed to explain its unexplored pathway in AML and detect its prognostic role and immunophenotypic association
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None