Investigation of cytogenetic markers in neonatal blood spots and of aberrant protein expression in bone marrow from children with leukemia
Author: Mattsson, Kristin
Date: 2018-11-23
Location: Sal C187, Karolinska Universitetssjukhuset, Huddinge
Time: 10.00
Department: Inst för klinisk vetenskap, intervention och teknik / Dept of Clinical Science, Intervention and Technology
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Thesis (489.8Kb)
Abstract
The general aim of this thesis was to contribute to a better understanding of the development and progression of leukemia in children. Biological markers identified in children with leukemia can contribute to the understanding of leukemic development.
Several studies have traced biological markers associated with leukemia back to a prenatal origin by analyzing neonatal blood spots (NBSs) indicating that these markers are early events in leukemogenesis. The fusion gene STIL-TAL1 occurs with a frequency of 11-27% at diagnosis of T-cell acute lymphoblastic leukemia (ALL) in children. The developmental timing of this fusion gene is unknown yet, STIL-TAL1 is exclusively found in T-cell ALL hence could be a key event in development of this type of leukemia.
Response to antileukemic treatment is important for prognosis in leukemia, but also specific molecular cytogenetic markers are important for classification and risk assessment. Mutations in the tumor suppressor gene TP53 are the most common genetic aberrations in cancer and analysis of altered expression of its protein product p53 has shown to have potential as a predicitve marker for adverse outcome in leukemic patients.
In scientific paper I, we investigated if the fusion gene STIL-TAL1 is present early in life by analyzing NBSs from 38 patients who developed T-cell ALL in childhood. DNA was extracted from the NBSs and analyzed for the fusion gene STIL-TAL1 by nested polymerase chain reaction and electrophoresis. We could not detect the presence of STIL-TAL1 in any of the 38 neonatal blood spots from pediatric T-cell ALL patients, indicating that STIL-TAL1 most probably is a post-natal event in development of T-cell ALL in children
In scientific paper II, III and IV we investigated if alterations in expression of specific cell cycle regulating proteins can predict relapse after hematopoietic stem cell transplantation (HSCT). Protein expression of p53 were analyzed in 33 patients with rare myeloid malignancies, 34 patients with acute myeloid leukemia (AML) and in 46 patients with B-cell ALL respectively. Protein expression was analyzed by immunohistochemistry (IHC) on tissue micro arrays. In study II, increased expression at diagnosis significantly predicted relapse after HSCT in children with rare myeloid malignancies. In study III, we found a higher p53 expression at three to six months after HSCT in the AML patients that relapsed compared to the group of patients who did not relapse. In study IV we found that an intense expression of p53 protein within three months after HSCT predicted relapse in patients with
In summary, we conclude that aberrant protein expression of p53, analyzed by IHC which is a well-established method available at most hematological laboratories, may have potential as a prognostic marker to predict relapse after HSCT in pediatric leukemia.
Several studies have traced biological markers associated with leukemia back to a prenatal origin by analyzing neonatal blood spots (NBSs) indicating that these markers are early events in leukemogenesis. The fusion gene STIL-TAL1 occurs with a frequency of 11-27% at diagnosis of T-cell acute lymphoblastic leukemia (ALL) in children. The developmental timing of this fusion gene is unknown yet, STIL-TAL1 is exclusively found in T-cell ALL hence could be a key event in development of this type of leukemia.
Response to antileukemic treatment is important for prognosis in leukemia, but also specific molecular cytogenetic markers are important for classification and risk assessment. Mutations in the tumor suppressor gene TP53 are the most common genetic aberrations in cancer and analysis of altered expression of its protein product p53 has shown to have potential as a predicitve marker for adverse outcome in leukemic patients.
In scientific paper I, we investigated if the fusion gene STIL-TAL1 is present early in life by analyzing NBSs from 38 patients who developed T-cell ALL in childhood. DNA was extracted from the NBSs and analyzed for the fusion gene STIL-TAL1 by nested polymerase chain reaction and electrophoresis. We could not detect the presence of STIL-TAL1 in any of the 38 neonatal blood spots from pediatric T-cell ALL patients, indicating that STIL-TAL1 most probably is a post-natal event in development of T-cell ALL in children
In scientific paper II, III and IV we investigated if alterations in expression of specific cell cycle regulating proteins can predict relapse after hematopoietic stem cell transplantation (HSCT). Protein expression of p53 were analyzed in 33 patients with rare myeloid malignancies, 34 patients with acute myeloid leukemia (AML) and in 46 patients with B-cell ALL respectively. Protein expression was analyzed by immunohistochemistry (IHC) on tissue micro arrays. In study II, increased expression at diagnosis significantly predicted relapse after HSCT in children with rare myeloid malignancies. In study III, we found a higher p53 expression at three to six months after HSCT in the AML patients that relapsed compared to the group of patients who did not relapse. In study IV we found that an intense expression of p53 protein within three months after HSCT predicted relapse in patients with
In summary, we conclude that aberrant protein expression of p53, analyzed by IHC which is a well-established method available at most hematological laboratories, may have potential as a prognostic marker to predict relapse after HSCT in pediatric leukemia.
List of papers:
I. Gustafsson B, Mattsson K, Bogdanovic G, Leijonhufvud G, Honkaniemi E, Ramme K, Ford A.M. Origins of STIL‐TAL1 fusion genes in children who later developed paediatric T‐cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots. Pediatric Blood & Cancer. 2018 Nov; 65(11):e27310.
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II. Honkaniemi E, Mattsson K, Barbany G, Sander B and Gustafsson B. Elevated p53 protein expression; a predictor of relapse in rare chronic myeloid malignancies in children? Pediatric Hematology and Oncology. 2014 May; 31(4):327-39.
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III. Mattsson K, Honkaniemi E, Barbany G. & Gustafsson B. Increased p53 protein expression as a potential predictor of early relapse after hematopoietic stem cell transplantation in children with acute myelogenous leukemia. Pediatr. Transplant. 2015 October; 19, 767–775.
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IV. Mattsson K, Honkaniemi E, Ramme K, Barbany G, Sander B and Gustafsson B. Strong expression of p53 protein in bone marrow samples after hematopoiteic stem cell transplantation indicates risk of relapse in pediatric acute lymphoblastic leukemia patients. [Submitted]
I. Gustafsson B, Mattsson K, Bogdanovic G, Leijonhufvud G, Honkaniemi E, Ramme K, Ford A.M. Origins of STIL‐TAL1 fusion genes in children who later developed paediatric T‐cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots. Pediatric Blood & Cancer. 2018 Nov; 65(11):e27310.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Honkaniemi E, Mattsson K, Barbany G, Sander B and Gustafsson B. Elevated p53 protein expression; a predictor of relapse in rare chronic myeloid malignancies in children? Pediatric Hematology and Oncology. 2014 May; 31(4):327-39.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Mattsson K, Honkaniemi E, Barbany G. & Gustafsson B. Increased p53 protein expression as a potential predictor of early relapse after hematopoietic stem cell transplantation in children with acute myelogenous leukemia. Pediatr. Transplant. 2015 October; 19, 767–775.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Mattsson K, Honkaniemi E, Ramme K, Barbany G, Sander B and Gustafsson B. Strong expression of p53 protein in bone marrow samples after hematopoiteic stem cell transplantation indicates risk of relapse in pediatric acute lymphoblastic leukemia patients. [Submitted]
Institution: Karolinska Institutet
Supervisor: Gustafsson, Britt
Co-supervisor: Ramme, Kim; Barbany, Gisela
Issue date: 2018-10-31
Rights:
Publication year: 2018
ISBN: 978-91-7831-195-8
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