View source for HAEM4:T-ALL/MEF2C

==Primary Author(s)*==

Ashwini Yenamandra PhD FACMG

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==Cancer Category/Type==

T- Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL)

==Cancer Sub-Classification / Subtype==

MEF2C

==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 [1].  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 [11]. 

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)[17]. 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 [11]. MEF2C overexpression found to be correlated with CDKN1B deletions early and immature T-ALL and may indicate a poor response to glucocorticoid treatment [7]. Colomer-Lahiguera S, et al.,[7] 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 [11]. 

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[11].

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) [4]. It is localized to chromosome 5q14.3 region and plays an important role in myogenesis [4]. 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 [5].  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 ([14].

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 [17].

==Synonyms / Terminology==

N/A

==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 [1].  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==

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 [1].

==Sites of Involvement==

Bone marrow, lymph node, extra nodal and mediastinal (thymic) involvement [1].

==Morphologic Features==

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 [1].

==Immunophenotype==

Put your text here and/or fill in the table

{| class="wikitable sortable"
|-
! Finding   !! Marker
|-
|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
|-
|Negative (subset) || CD117
|}

==Chromosomal Rearrangements (Gene Fusions)==

Not Applicable

==Characteristic Chromosomal Aberrations / Patterns==

Transcriptional activation by NKX2-5 and/or deletion of chromosome 5q14.3 region [4].

==Genomic Gain/Loss/LOH==

Not Available



{| class="wikitable sortable"
|-
! Chromosome Number !! Gain/Loss/Amp/LOH !! Region
|-
|EXAMPLE 8 || EXAMPLE Gain || EXAMPLE chr8:0-1000000
|-
|EXAMPLE 7 || EXAMPLE Loss || EXAMPLE chr7:0-1000000
|}

==Gene Mutations (SNV/INDEL)==

Not Available.





{| class="wikitable sortable"
|-
! 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%
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
! Type !! Gene/Region/Other
|-
| Concomitant Mutations || EXAMPLE IDH1 R123H
|-
| Secondary Mutations || EXAMPLE Trisomy 7
|-
|Mutually Exclusive || EXAMPLE EGFR Amplification
|}

==Epigenomics (Methylation)==

Not Available.

==Genes and Main Pathways Involved==

Transcriptional activation of heart specific homeobox gene NKX2-5 and early thymocyte gene GFI1B [4].

Nagel et al., [4] 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 [1]. Despite the initial poor response to Glucocorticoids, 75% of patients with MEF2C dysregulated T-ALL had long term remission [7]. Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored [17]. BCL2 inhibitors were suggested as a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C [17]. 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 [11].

==Familial Forms==

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]

==Other Information==

MEF2C expression was also reported in a subset of pediatric and adult AML patients[8].

==Links==
Put your links here (use "Link" icon at top of page)

==References==
<references />
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

5. http://www.cancerindex.org/geneweb/MEF2C.htm

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.   

15. https://en.wikipedia.org/wiki/MEF2CWikipedia 

16. https://rarediseases.info.nih.gov/

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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