Immunophenotyping and Xist Gene in AML

NCT04288739 | Unknown

• 1 other identifier: AssiutU-CP-Xist 90
• Study Type: observational
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors (blasts) in the bone marrow and peripheral blood.Several 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 MPN/MDS) 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.

Conditions

Acute Myeloid Leukemia

Keywords

AML

Outcome Measures

Primary Outcomes (2)

• Identify Xist gene by FISH in AML

  Identify X- inactive specific transcript (Xist) gene by fluorescence insitu hybridization (FISH) in AML

  2 years

• Integrating multiple strategies ( immunophenotypic fingerprint by flowcytometry and Xist gene by FISH) in AML

  Integrating multiple strategies by Identification through multiparametric flow cytometry atdiagnosis of an immunophenotypic fingerprint associated with Xist gene abnormalities, detected by FISH, as a novel and simplified tool with improved sensitivity, to detect these abnormalities may allowing patient stratification and risk adapted treatment with potential impact on outcome of the disease.

  2 years

Study Arms (1)

Acute Myeloid Leukemia (AML) group

patients who are diagnosed as Acute Myeloid Leukemia (AML) based on peripheral blood, bone marrow, immunophenotyping and who fulfill the WHO 2016 criteria. Complete blood count (CBC), bone marrow aspirate, flow cytometric immunophenotyping, cytogenetic analysis and fluorescence in situ hybridization (FISH) for XIST gene will be performed for all AML patients in the study.

Diagnostic Test: flow cytometric immunophenotyping; Genetic: Xist gene by fluorescence insitu hybridization

Interventions

flow cytometric immunophenotyping DIAGNOSTIC_TEST

Flow cytometric (FCM) immunophenotypic analysis of peripheral blood or bone marrow aspiration samples will be performed using a panel of monoclonal antibodies (HLA DR, CD34, CD117, Cyto MPO, CD13, CD33, CD3, CD4, CD8, CD10, CD19, CD5, CD14, CD64, CD36, CD235a, cyto CD41, cyto CD61).

Acute Myeloid Leukemia (AML) group

Xist gene by fluorescence insitu hybridization GENETIC

Fluorescence in situ hybridization (FISH) is a kind of cytogenetic technique that allows the visualization of defined nucleic acid sequences in particular cellular or chromosomal sites by hybridization of complementary fluorescently labeled probe sequences within intact metaphase or interphase cells. The fluorescent probes are nucleic acid labeled with fluorescent groups and can bind to specific DNA/RNA sequences. Fluorescence microscopy can be used to find out where the fluorescent probe is bound to the chromosomes.

Also known as: FISH

Acute Myeloid Leukemia (AML) group

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

AML patients, who fulfill the WHO 2016 criteria

You may qualify if:

• AML patients, who fulfill the WHO 2016 criteria

You may not qualify if:

• patients with other hematological nepolasms (ALL,CLL, plasma cell myeloma)

Sponsors & Collaborators

• Assiut University: lead

Study Sites (1)

Faculty of medicine

Asyut, 71515, Egypt

Location

Related Publications (9)

• Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol. 2018 Oct;93(10):1267-1291. doi: 10.1002/ajh.25214.

  PMID: 30328165 BACKGROUND

• Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015 Sep 17;373(12):1136-52. doi: 10.1056/NEJMra1406184. No abstract available.

  PMID: 26376137 BACKGROUND

• Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, Henley SJ, Anderson RN, Firth AU, Ma J, Kohler BA, Jemal A. Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics. Cancer. 2018 Jul 1;124(13):2785-2800. doi: 10.1002/cncr.31551. Epub 2018 May 22.

  PMID: 29786848 BACKGROUND

• Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21.

  PMID: 25328522 BACKGROUND

• Angelini DF, Ottone T, Guerrera G, Lavorgna S, Cittadini M, Buccisano F, De Bardi M, Gargano F, Maurillo L, Divona M, Noguera NI, Consalvo MI, Borsellino G, Bernardi G, Amadori S, Venditti A, Battistini L, Lo-Coco F. A Leukemia-Associated CD34/CD123/CD25/CD99+ Immunophenotype Identifies FLT3-Mutated Clones in Acute Myeloid Leukemia. Clin Cancer Res. 2015 Sep 1;21(17):3977-85. doi: 10.1158/1078-0432.CCR-14-3186. Epub 2015 May 8.

  PMID: 25957287 BACKGROUND

• Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013 Feb 14;152(4):727-42. doi: 10.1016/j.cell.2013.01.034.

  PMID: 23415223 BACKGROUND

• Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, Willard HF. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527-42. doi: 10.1016/0092-8674(92)90520-m.

  PMID: 1423611 BACKGROUND

• Wutz A, Rasmussen TP, Jaenisch R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet. 2002 Feb;30(2):167-74. doi: 10.1038/ng820. Epub 2002 Jan 7.

  PMID: 11780141 BACKGROUND

• Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.

  PMID: 27069254 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood or bone marrow aspirate samples

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Shaaban R. Helal, MD

  faculty of medicine

  STUDY DIRECTOR

Central Study Contacts

Alaa M. Kassem, M.Sc

CONTACT

+201010328237; alaakassem363@yahoo.com

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant lecturer

Study Record Dates

• First Submitted: February 23, 2020
• First Posted: February 28, 2020
• Study Start: October 2, 2020
• Primary Completion: May 30, 2022
• Study Completion: December 31, 2022
• Last Updated: July 9, 2020

Record last verified: 2020-07

Locations

EG (1)