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Early T-cell precursor acute lymphoblastic leukemia

Written2017-02Steven Richebourg
Laboratoire de cytogénétique onco-hématologique, Département de pathologie, Hôpital du Saint Sacrement, CHU de Québec Université Laval, 1050, Chemin Sainte Foy, Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec, G1S4L8 Québec, Qc, Canada; steven.richebourg.cha@ssss.gouv.qc.ca

Abstract Review on early T-cell precursor acute lymphoblastic leukemia, with data on clinics and the genes possibly involved.

Keywords T-cell; acute lymphoblastic leukemia

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
Atlas_Id 1667
Other namesEarly T-cell precursor lymphoblastic leukemia/ETP-ALL/ETP T-ALL

Clinics and Pathology

Note Identified in 2009 from gene expression profiling data, Early T cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) represents a subset of T-ALL sharing transcriptional and immunophenotypic similarities with early T-cell precursors (Coustan-Smith et al., 2009).
ETP-ALL is currently defined by a distinctive phenotype characterized by a lack of expression of the T-lineage cell surface markers CD1a and CD8, weak or absent expression of CD5 and aberrant expression of one or more myeloid or stem cell markers (Coustan-Smith et al., 2009).
Since the description, genetic alterations and prognostic data have been reported in literature improving our understanding of this subgroup. Therefore, ETP-ALL has been included as a provisional entity in the 2016 revision of the WHO classification of Acute Leukemias (Arber et al., 2016).
Phenotype / cell stem origin Early T-cell precursors (ETPs) are immature progenitors that have recently immigrated from the bone marrow to the thymus and which retain a multilineage differentiation potential (T-lymphoid, natural killer, dendritic and myeloid cell differentiation potential). Animal model based studies of ETPs demonstrate similarities with immature myeloid progenitors and hematopoietic stem cells (Bell and Bandhoola, 2008; Wada et al., 2008). Because gene expression profiling is not part of routine laboratory investigations, ETP-ALL cases are currently identified through the phenotype of blast cells : CD1a-, CD8-, CD5- /weak, and positivity for one or more stem cell and/or myeloid antigens (CD117, CD34, HLA-DR, CD13, CD33, CD11b, and/or CD65) (Coustan-Smith et al., 2009; Chopra et al., 2014). ETP-ALL typically also express CD2, CD7 and cytoplasmic CD3 and may express CD4.
Epidemiology Initially described from children ALL cohorts, ETP-ALL have also been identified in adults. Frequency of ETP-ALL varies among studies around 10-15% of T ALL.
In children, ETP-ALL has been reported in 11% to 16% of T-ALL (Coustan-Smith et al., 2009; Patrick et al., 2014).
In adults, ETP-ALL frequency ranges from 7,4% (Neumann et al., 2012) to 17% of T-ALL (Jain et al., 2016).
Based on gene expression profiling, some authors suggest that there is an immature signature related to ETPs (called "near ETP' or "close to ETP") which may be more prevalent (Van Vlierberghe et al., 2013; Haydu and Ferrando, 2013).
Clinics Most studies report no significant association between ETP-ALL signature and clinical features including sex, age, white blood cell count, and central nervous system involvement (Coustan-Smith et al., 2009; Inukai et al., 2012; Neumann et al., 2012). Though, two no recurrent features were identified : an older age in paediatric population (Coustan-Smith et al., 2009) and a lower frequency of mediastinal mass at diagnosis in adult population (Neumann et al., 2012).
 
Courtesy Linda Boulay and Frédéric Barabé, Flow Cytometry Laboratory, Hôpital du Saint Sacrement, CHU de Québec Université Laval
Cytology No specific morphologic features have been reported to date.
Treatment Since there is no consensus on the prognosis (see below), no specific protocol is recommended. Because of the trend to negative impact on prognosis, some authors suggest that new therapeutic strategies are needed to improve the outcomes of ETP-ALL (Jain et al., 2016; Neumann et al., 2013), including the use myeloid-targeted therapies such as tyrosine kinase inhibitors (Neumann et al., 2012; Neumann et al., 2013; Zhang et al., 2012)
Prognosis There is currently no consensus on the prognosis of ETP-ALL.
Initial prognostic studies between 2009 and 2012 reported a negative prognostic impact on response rate and survival (Coustan-Smith et al., 2009, Inukai et al., 2012; Ma et al., 2012) and a higher risk of relapse (Allen and al., 2013).
These data were not confirmed in more recent studies with larger cohorts (Brent et al., 2014; Patrick et al., 2014; Zuurbier et al., 2014).
However, in 2016, a MD Anderson study reported again a negative prognostic impact on the response rate and the overall survival of patients with ETP-ALL (Jain et al., 2016).

Cytogenetics

Note No specific cytogenetic abnormality is associated with ETP-ALL subtype.
In most studies, ETP-ALL patients present highly variable karyotypes with remarkably a lower frequency of classic recurrent rearrangements associated with T-ALL (Patrick et al., 2014).
Coustan Smith and al reported a higher frequency of deletion 13q (Coustan-Smith et al., 2009) and Patrick et al a higher frequency of KMT2A rearrangements (Patrick et al., 2014).
SNP analysis demonstrated a higher frequency of copy number alterations in ETP-ALL vs non ETP-ALL (Coustan-Smith et al., 2009).

Genes involved and Proteins

Note ETP-ALL subgroup is characterized by a high genetic heterogeneity and present a distinct genomic profile defined by a lower incidence of typical mutations associated with T ALL such as NOTCH1 or FBXW7 and a high frequency of myeloid associated gene mutations ( FLT3, RAS mutations, DNMT3A, IDH1 / IDH2 mutations) (Neumann et al., 2013; Van Vlierberghe et al., 2011; Zhang et al., 2012).
Whole exome and whole genome sequencing approaches identified mutations in multiple pathways including mutations in genes activating cytokine receptor and RAS signalling ( NRAS , KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating haematopoietic transcription factors ( GATA3, ETV6, RUNX1, IKZF1 and EP300) and in epigenetic regulators (EZH2, EED, SUZ12, SETD2 and EP300) (Zhang et al., 2012)

Bibliography

Early T-cell precursor leukemia/lymphoma in adults and children
Allen A, Sireci A, Colovai A, Pinkney K, Sulis M, Bhagat G, Alobeid B
Leuk Res 2013 Sep;37(9):1027-34
PMID 23827350
 
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW
Blood 2016 May 19;127(20):2391-405
PMID 27069254
 
The earliest thymic progenitors for T cells possess myeloid lineage potential
Bell JJ, Bhandoola A
Nature 2008 Apr 10;452(7188):764-7
PMID 18401411
 
T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children's Oncology Group (COG) Study AALL0434
Brent L. Wood, Stuart S. Winter, Kimberly P. Dunsmore, Meenakshi Devidas, Si Chen, Barbara Asselin, Natia Esiashvili, Mignon L. Loh, Naomi J. Winick, William L. Carroll, Elizabeth A. Raetz and Stephen P. Hunger
Blood 2014 124:1
 
Immunophenotypic analysis of T-acute lymphoblastic leukemia
Chopra A, Bakhshi S, Pramanik SK, Pandey RM, Singh S, Gajendra S, Gogia A, Chandramohan J, Sharma A, Kumar L, Seth R, Rai S, Kumar R
A CD5-based ETP-ALL perspective of non-ETP T-ALL Eur J Haematol
PMID 24329989
 
Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia
Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D
Lancet Oncol 2009 Feb;10(2):147-56
PMID 19147408
 
Early T-cell precursor acute lymphoblastic leukaemia
Haydu JE, Ferrando AA
Curr Opin Hematol 2013 Jul;20(4):369-73
PMID 23695450
 
Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15
Inukai T, Kiyokawa N, Campana D, Coustan-Smith E, Kikuchi A, Kobayashi M, Takahashi H, Koh K, Manabe A, Kumagai M, Ikuta K, Hayashi Y, Tsuchida M, Sugita K, Ohara A
Br J Haematol 2012 Feb;156(3):358-65
PMID 22128890
 
Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype
Jain N, Lamb AV, O'Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, Thomas D, Rytting M, Borthakur G, Kadia T, Cortes J, Kantarjian HM, Khoury JD
Blood 2016 Apr 14;127(15):1863-9
PMID 26747249
 
Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia
Ma M, Wang X, Tang J, Xue H, Chen J, Pan C, Jiang H, Shen S
Front Med 2012 Dec;6(4):416-20
PMID 23065427
 
FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors
Neumann M, Coskun E, Fransecky L, Mochmann LH, Bartram I, Sartangi NF, Heesch S, Gökbuget N, Schwartz S, Brandts C, Schlee C, Haas R, Dührsen U, Griesshammer M, Döhner H, Ehninger G, Burmeister T, Blau O, Thiel E, Hoelzer D, Hofmann WK, Baldus CD
PLoS One 2013;8(1):e53190
PMID 23359050
 
Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations
Neumann M, Heesch S, Schlee C, Schwartz S, Gökbuget N, Hoelzer D, Konstandin NP, Ksienzyk B, Vosberg S, Graf A, Krebs S, Blum H, Raff T, Brüggemann M, Hofmann WK, Hecht J, Bohlander SK, Greif PA, Baldus CD
Blood 2013 Jun 6;121(23):4749-52
PMID 23603912
 
Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003
Patrick K, Wade R, Goulden N, Mitchell C, Moorman AV, Rowntree C, Jenkinson S, Hough R, Vora A
Br J Haematol 2014 Aug;166(3):421-4
PMID 24708207
 
ETV6 mutations in early immature human T cell leukemias
Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M, Tosello V, Della Gatta G, Paietta E, Racevskis J, Wiernik PH, Luger SM, Rowe JM, Rue M, Ferrando AA
J Exp Med 2011 Dec 19;208(13):2571-9
PMID 22162831
 
Adult T-cell progenitors retain myeloid potential
Wada H, Masuda K, Satoh R, Kakugawa K, Ikawa T, Katsura Y, Kawamoto H
Nature 2008 Apr 10;452(7188):768-72
PMID 18401412
 
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG
Nature 2012 Jan 11;481(7380):157-63
PMID 22237106
 
Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors
Zuurbier L, Gutierrez A, Mullighan CG, Canté-Barrett K, Gevaert AO, de Rooi J, Li Y, Smits WK, Buijs-Gladdines JG, Sonneveld E, Look AT, Horstmann M, Pieters R, Meijerink JP
Haematologica 2014 Jan;99(1):94-102
PMID 23975177
 

Citation

This paper should be referenced as such :
Richebourg S
Early T-cell precursor acute lymphoblastic leukemia;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/EarlyTcellALLID1667.html


External links

arrayMapMorph ( 9837/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaseEarly T-cell precursor acute lymphoblastic leukemia
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