Clinical trial NCT04092348: FoxO3a and PU.1 in Acute Lymphoblastic Leukemia
Official title: Value of FoxO3a and PU.1 Expression in Pediatric Acute Lymphoblastic Leukemia
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Acute Lymphoblastic Leukemia
Lead sponsor: Assiut University
Sponsor class: OTHER
First posted: 2019-09-17
Enrollment: 53
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: * cases

  1. inclusion criteria: children aged 2-17 years and diagnosed as new cases of acute lymphoblastic leukemia
  2. exclusion criteria:

     1. age more than 17 years
     2. presence of other hematological disorders, history of other malignancies ,or relapsed ALL
     3. patients under chemotherapy or radiotherapy
* controls (healthy age- and sex-matched children without ahistory of any malignancies)

Brief summary: Acute Lymphoblastic Leukemia (ALL) is one of the four major types of leukemia which is common in both children and adolescents; however, it is the most common pediatric malignancy diagnosed in children younger than 20 years .The disease pathogenesis results from blockade at any stages of normal lymphoid differentiation with uncontrolled proliferation of lymphoid cells. According to the World Health Organization (WHO) definition, ALL is categorized in B-Lymphoblastic Leukemia (B-ALL) And T-Lymphoblastic Leukemia (T-ALL), originated from B- and T-Lineage lymphoid precursor cells, respectively.

Detailed description: Proto-oncogenes and tumor suppressor genes are the most important genes involved in leukemogenesis , which their alterations disrupt normal regulatory processes such as self-renewal, proliferation, differentiation and apoptosis in target cells. Among those genes FoxO3a gene and PU.1 gene.

FoxO(Fork head box ,class O) transcription factors function as a tumor suppressor gene and are important for stem cell maintenance.They are key regulators of the cellular differentiation, growth, survival, cell cycle, metabolism, and cellular stress. There are four members of the foxO transcription factors in humans : foxO1, foxO3a, foxO4, foxO6 .FoxO3a is expressed in various tissues including B - and T-lymphoid cells. Over expression of FoxO3a in B and T cell lines induces cell cycle arrest in G1 phase , so it inhibits cell proliferation . FoxO3a is an important target of PI3K/AKT signaling pathway,which is hyperactivated in various types of cancers .Hyperactivation of this pathway in leukemia leads to inactivation of foxO3a in leukemic cells and enhances tumor growth .

PU .1(Purine-rich box 1) is a member of the E26 transformation-specific (ETS) Family . Normal hematopoiesis is securely controlled by asmall number of lineage-specific transcription factors, so that the disturbed expression or function of this group may be involved in the development of leukemia . PU.1 plays an important role in hematopiotic stem cell (HSC) self renewal and in myeloid and B-lymphoid differentiation. It controls the expression of several genes involved in hematopoiesis.

Eligibility criteria: Inclusion Criteria:

* children aged 2-17 years and diagnosed as new cases of acute lymphoblastic leukemia

Exclusion Criteria:

1. age more than 17 years
2. presence of other hematological disorders, history of other malignancies ,or relapsed ALL
3. patients under chemotherapy or radiotherapy

Primary outcomes:
measure: FoxO3a and PU.1 levels in acute lymphoblastic leukemia
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
citation: Ferber EC, Peck B, Delpuech O, Bell GP, East P, Schulze A. FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 2012 Jun;19(6):968-79. doi: 10.1038/cdd.2011.179. Epub 2011 Dec 2.
citation: Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013 Jun 1;381(9881):1943-55. doi: 10.1016/S0140-6736(12)62187-4. Epub 2013 Mar 22.
citation: Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA, Hedrick SM. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol. 2009 Feb;10(2):176-84. doi: 10.1038/ni.1689. Epub 2009 Jan 11.
citation: Pui CH. Acute lymphoblastic leukemia: introduction. Semin Hematol. 2009 Jan;46(1):1-2. doi: 10.1053/j.seminhematol.2008.09.011. No abstract available.
citation: Xie Y, Davies SM, Xiang Y, Robison LL, Ross JA. Trends in leukemia incidence and survival in the United States (1973-1998). Cancer. 2003 May 1;97(9):2229-35. doi: 10.1002/cncr.11316.
citation: Yang XB, Zhao JJ, Huang CY, Wang QJ, Pan K, Wang DD, Pan QZ, Jiang SS, Lv L, Gao X, Chen HW, Yao JY, Zhi M, Xia JC. Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients. PLoS One. 2013 Oct 23;8(10):e78158. doi: 10.1371/journal.pone.0078158. eCollection 2013.
citation: Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011 Nov;1813(11):1978-86. doi: 10.1016/j.bbamcr.2011.03.010. Epub 2011 Mar 31.
citation: Ausserlechner MJ, Salvador C, Deutschmann A, Bodner M, Viola G, Bortolozzi R, Basso G, Hagenbuchner J, Obexer P. Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL and Noxa. Oncotarget. 2013 Jul;4(7):995-1007. doi: 10.18632/oncotarget.953.
citation: Chiaretti S, Zini G, Bassan R. Diagnosis and subclassification of acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis. 2014 Nov 1;6(1):e2014073. doi: 10.4084/MJHID.2014.073. eCollection 2014.