title: Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences.
abstract: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is characterized by chromosomal rearrangements possibly enforcing arrest at specific development stages. We studied the relationship between molecular-cytogenetic abnormalities and T-cell development stage to investigate whether arrest at specific stages can explain the prognostic significance of specific abnormalities. We extensively studied 72 pediatric T-ALL cases for genetic abnormalities and expression of transcription factors, NOTCH1 mutations and expression of specific CD markers. HOX11 cases were CD1 positive consistent with a cortical stage, but as 4/5 cases lacked cytoplasmatic-beta expression, developmental arrest may precede beta-selection. HOX11L2 was especially confined to immature and pre-AB developmental stages, but 3/17 HOX11L2 mature cases were restricted to the gammadelta-lineage. TAL1 rearrangements were restricted to the alphabeta-lineage with most cases being TCR-alphabeta positive. NOTCH1 mutations were present in all molecular-cytogenetic subgroups without restriction to a specific developmental stage. CALM-AF10 was associated with early relapse. TAL1 or HOX11L2 rearrangements were associated with trends to good and poor outcomes, respectively. Also cases with high vs low TAL1 expression levels demonstrated a trend toward good outcome. Most cases with lower TAL1 levels were HOX11L2 or CALM-AF10 positive. NOTCH1 mutations did not predict for outcome. Classification into T-cell developmental subgroups was not predictive for outcome.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Grotel
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
authors.forename: H B
authors.initials: HB
authors.lastname: Beverloo
authors.forename: J G C A M
authors.initials: JG
authors.lastname: Buijs-Gladdines
authors.forename: N B
authors.initials: NB
authors.lastname: Burger
authors.forename: M
authors.initials: M
authors.lastname: Passier
authors.forename: E M
authors.initials: EM
authors.lastname: van Lieshout
authors.forename: W A
authors.initials: WA
authors.lastname: Kamps
authors.forename: A J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: M M
authors.initials: MM
authors.lastname: van Noesel
authors.forename: R
authors.initials: R
authors.lastname: Pieters
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019070:Cell Lineage; D002648:Child; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C114359:AF10-CALM fusion protein, human; C497761:NOTCH1 protein, human; C489494:TLX3 protein, human; C067143:TAL1 protein, human