Ashwini Yenamandra PhD FACMG
T- Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL)
Cancer Sub-Classification / Subtype
Definition / Description of Disease
T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL)
T-ALL and T-LBL are heterogeneous neoplasms of immature T-cell precursors (lymphoblasts) that are committed to the T-cell lineage [1-13]. It is an aggressive disease with poor prognosis. Multiple genetic events in a multistep process leads to the transformation of the neoplasm [1-17]. Immature T-ALL subtypes with gene expression signatures including TAL/LMO1, TLX1, HOXA clusters that are specific for various stages of thymocyte development and overexpression of NKX2-2, NKX1 and MEF2C have been described in T-ALL and T-LBL [1-14].
T-ALL is less common than B-ALL, accounts for 25% adults and 15% pediatric of total ALL cases [1, 2]. It is reported mostly in adolescents with a male predominance . T-LBL accounts for 85-90% of all lymphoblastic lymphoma, 30% of patients do relapse either during treatment or within two years [1-15]. Three distinct immature T-cell acute lymphoblastic leukemia entities consisting have been reported .
The three entities are: 1. Early T-cell precursor immunophenotype or expression profile, 2. Immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) 3. Non-rearranged TRG@ loci.
A high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL) is Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL). Early T-cell precursor acute lymphoblastic leukemia cases overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are a single disease entity . MEF2C overexpression found to be correlated with CDKN1B deletions early and immature T-ALL and may indicate a poor response to glucocorticoid treatment . Colomer-Lahiguera S, et al., suggest analysis of MEF2C expression and highly standardized immunophenotyping to refine classification of T-ALL subtypes.
Patients that do not have TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity .
Early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33.
Myocyte enhancer factor C (MEF2C) is a transcription part of the MEF2 protein family, a group of transcriptional regulators including four different isoforms (MEF2A-D) . It is localized to chromosome 5q14.3 region and plays an important role in myogenesis . MEF2C is expressed during hematopoiesis in multi-potent B progenitor cells but not in T-cell development [2-4]. MEF2C has both trans-activating and DNA binding activities . Abnormal expression of MEF2C in T-ALL is an indication of its aberration and results in inhibition of apoptosis [1-14].
MEF2C is activated by multiple mechanisms including NKX2-5 (transcriptional activation factor and maps to 5q35 region) or chromosomal deletion of 5q14 region [2-4]. GF11B, TAL1, and LYl1 gene loci activate expression of MEF2C where as STAT5, HOXA9, and HOXA10 gene loci inhibit expression of MEF2C via N- MYC [2-4, 14-15]. MEF2C is probably the oncogene for immature T-ALL cases that seems to provide a T cell differentiation block at the immature stage (.
Gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than in typical T-ALL .
Synonyms / Terminology
Epidemiology / Prevalence
T-ALL is less common than B-ALL, accounts for 25% adults and 15% pediatric of total ALL cases [1, 2]. It is reported mostly in adolescents with a male predominance . T-LBL accounts for 85-90% of all lymphoblastic lymphoma, 30% of patients do relapse either during treatment or within two years. [1, 14] Frequency of MEF2C is not well understood yet.
Clinical features include high leukocyte count, mediastinal mass or other tissues, hepatosplenomegaly, lymphadenopathy, pleural effusions and respiratory emergency. T-ALL usually has rapid progression of disease .
Sites of Involvement
Bone marrow, lymph node, extra nodal and mediastinal (thymic) involvement .
T-ALL/T-LBL have morphologically similar lymphoblasts. The lymphoblasts are small to medium cells with scant cytoplasm, moderately condensed to dispersed chromatin and small s nucleoli. In T-ALL, Bone marrow (BM) or Peripheral blood (PB) is involved and in T-LBL thymus, nodal or extra nodal tissues along with BM and PB are involved .
Put your text here and/or fill in the table
|Positive (universal)||CD1a,CD2, CD3, CD4, CD5, Cd6, Cd7, CD8, CD13, CD33, CD34, Class II HLA-DR|
|Positive (subset)||CD10, Mature basophils can be CD25+ and CD117-, mast cells can be CD117+ and CD25+, blasts can be CD9+ and TdT+.|
|Negative (universal)||No B or T -lymphoid markers|
Chromosomal Rearrangements (Gene Fusions)
Characteristic Chromosomal Aberrations / Patterns
Transcriptional activation by NKX2-5 and/or deletion of chromosome 5q14.3 region .
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000|
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000|
Gene Mutations (SNV/INDEL)
|Gene||Mutation||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%|
|Concomitant Mutations||EXAMPLE IDH1 R123H|
|Secondary Mutations||EXAMPLE Trisomy 7|
|Mutually Exclusive||EXAMPLE EGFR Amplification|
Genes and Main Pathways Involved
Transcriptional activation of heart specific homeobox gene NKX2-5 and early thymocyte gene GFI1B .
Nagel et al.,  described the transcription binding site of NKX2-5 and GF11B to Exon 1a of first coding region of MECF2C and downstream deletion of 5q14 region in the LOUCY cell line.
Diagnostic Testing Methods
Morphology, IHC and genetic testing.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
Childhood T-ALL is considered as a high risk than B-ALL, may have higher risk of induction failure and early relapse . Despite the initial poor response to Glucocorticoids, 75% of patients with MEF2C dysregulated T-ALL had long term remission . Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored . BCL2 inhibitors were suggested as a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C . Immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients .
Deletion and mutations of MEF2C is clinically significant in congenital genetic disease and is characterized by intellectual disability, absent speech, stereotypic movements, epilepsy and unusual facial features [15, 16]
MEF2C expression was also reported in a subset of pediatric and adult AML patients.
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1. Borowitz MJ, et al., (2016).T-lymphoblastic leukemia/lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p209-212.
2. Nagel S, et al., (2011). Transcriptional deregulation of oncogenic myocyte enhancer factor 2C in T-cell acute lymphoblastic leukemia. Leukemia & Lymphoma, 52(2): 290–297, PMID 21261500.
3. Nagel S, et al., (2008). MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines. Leukemia 22: 600–607, PMID 18079734.
4. Nagel S, et al., (2011). Activation of Paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia. Leukemia & Lymphoma 52(7): 1348–1359, PMID 21425961
6. You ML. et al., (2015) T-lymphoblastic leukemia/lymphoma. Am J Clin Pathol 144(3) 411-22, PMID 26276771.
7. Colomer-Lahiguera S, et al., (2017). MEF2C-dysregulated pediatric T-cell acute lymphoblastic leukemia is associated with CDKN1B deletions and a poor response to glucocorticoid therapy. Leuk Lymphoma 58 (12): 2895–2904, PMID 28482719.
8. Laszlo GS, et al., (2015) High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse-risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. J. Hematology & Oncol 8:115, PMID 26487643.
9. Karman, et al., (2015) Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor sub clones and a high incidence of uniparental isodisomies affecting CDKN2A. J. Hem. Oncol 8:42, PMID 25903014.
10. Zeynep KA, et al., (2013) Comprehensive Analysis of Transcriptome Variation Uncovers Known and Novel Driver Events in T-Cell Acute Lymphoblastic Leukemia. PLOS genetics 9 :12, PMID 24367274.
11. Zuurbier L, et al., (2013) 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. Hematologica 99(1):94-102, PMID 23975177.
12. Paciorkowski AR, et al., (2013) MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics, 14(2): 99–111, PMID 23389741.
13. Vlierberghe PV, et al., (2012)The molecular basis of T cell acute lymphoblastic leukemia. J Clinical Investigation. 122(10):3398-406, PMID 23023710.
14. Homminga I, et al., (2011) Integrated Transcript and Genome Analyses Reveal NKX2-1 and MEF2C as Potential Oncogenes in T cell Acute Lymphoblastic Leukemia. Cancer Cell 19:484–497, PMID 21481790.
17. Kawashima-Goto S, et al., (2015) A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression? PLoS One 14:10(7), PMID 26172269.
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