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t(8;21)(q22;q22) RUNX1/RUNX1T1

Identity

 
  t(8;21)(q22;q22) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top) and Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap http://www.slh.wisc.edu/cytogenetics (middle and below); R- banding (middle) - above: Jean Loup Huret; 2nd row: - Courtesy Christiane Charrin; 3rd and 4th row: - Courtesy Roland Berger. Right: FISH - Courtesy Hossein Mossafa.

Clinics and Pathology

Disease ANLL
Phenotype / cell stem origin M2 mostly, rarely: M1 or M4
Epidemiology annual incidence: 1/106; 10% of ANLL, 40% of M2 ANLL; the most frequent anomaly in chilhood ANLL; seen in children and adults: mean age 30yrs, rare in elderly patients; male excess (4M/3F) is much less than sometimes claimed
Clinics chloromas
Cytology numerous and thin Auer rods; eosinophilia of the bone marrow; CD19 (early B) and CD56 (natural killer) may be expressed: the cell involved may be an early progenitor
 
Translocation t(8;21) is found in 5-12% of AML. Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is one of the best known and usually correlates with AML M2, with well defined and specific morphological features. The common morphological features include the presence of large blast cells with abundant basophilic cytoplasm, often containing numerous azurophilic granulations; few blasts in some cases show very large granules (pseudo-Chediak-Higashi granules), suggesting abnormal fusion. Auer rods are frequently found. In addition to the large blast cells, there are also some smaller blasts, predominantly found in the peripheral blood. Promyelocytes, myelocytes and mature granulocytes with variable dysplasia are seen in the bone marrow. These cells may show abnormal nuclear segmentation and/or cytoplasmic staining defects including homogeneous pink colored cytoplasm - Text and iconography Courtesy Georges Flandrin 2001.
Prognosis CR in most cases (90%); but relapse is frequent, and median survival -1.5yrs (adults) to 2yrs (children)- in the range with other ANLL in some series, relatively long median survival, especially in the adults for others; no adverse effect of additional chromosome anomalies

Cytogenetics

 
  t(8;21)(q22;q22) : cohybridization experiments using dJ155L8 (ETO) and dJ1107L6 (AML1); note the splitting of AML1 and colocalization on der(8) with ETO - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Cytogenetics Molecular cases with cryptic molecular translocation have been detected (similar to Ph negative CML with positive BCR-ABL) --> FISH use may be relevant
Additional anomalies sole anomaly in only 20%; additional anomalies: numerical in 2/3, structural in 1/3; loss of Y or X chromosome in half cases (1 X must be present), del(7q) or -7, +8, del (9q): 10% each.
Variants complex t(8;21;Var) involving a (variable) third chromosome have been described in 3%; part from chromosome 21 goes on der(8), part of the 8 on der (Var), and part of Var on der(21); therefore, the crucial event lies on der(8).

Genes involved and Proteins

Gene Name ETO
Location 8q22
Dna / Rna transcription is from telomere to centromere
Protein 3 proline rich domains, 2 Zn fingers, and in C-term, a PEST region; tissue restricted expression; nuclear localisation; putative transcription factor
Gene Name AML1
Location 21q22
Dna / Rna transcription is from telomere to centromere
Protein contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes

Result of the chromosomal anomaly

Hybrid gene
 
  RUNX1 (AML1) and RUNX1T1 (ETO) breakpoints in the t(8;21) / 5' RUNX1 - 3' RUNX1T1 fusion gene, and FISH - Courtesy Hossein Mossafa.
Description 5' AML1 - 3' ETO; breakpoints: at the very 5' end of ETO, between exons 5 and 6 in AML1
Detection RT-PCR in cases: 1- of typical cell morphology, but apparently without the t(8;21); 2- for minimal residual disease detection
  
Fusion Protein
Description the N-term runt domain from AML1 is fused to the 577 C-term residues from ETO; reciprocal product not detected; probable DNA binding role; the fusion protein retains the ability to recognize the AML1 concensus binding site (--> negative dominant competitor with the normal AML1) and to dimerize with the CBFb subunit
Oncogenesis probable altered transcriptional regulation of normal AML1 target genes
  

Other genes implicated (Data extracted from papers in the Atlas)

Genes RUNX1 CBFA2T3 CEBPA CSF1R RUNX1T1 IRF1 KIT SSX2IP ZFP36L1

Translocations implicated (Data extracted from papers in the Atlas)

 t(8;21)(q22;q22) RUNX1/RUNX1T1

External links

Mitelman database Mitelman database (CGAP - NCBI)
t(8;21)(q22;q22) - Mitelman database (CGAP - NCBI)
COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMapTopo ( C42) Morph ( 9896/3) - arrayMap (Zurich)
Other databaseETO/AML1 translocation (8/21) (Bari)

Bibliography

AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia.
Nucifora G, Rowley JD
Blood. 1995 ; 86 (1) : 1-14.
PMID 7795214
 
Molecular basis of the t(8;21) translocation in acute myeloid leukaemia.
Ohki M
Seminars in cancer biology. 1993 ; 4 (6) : 369-375.
PMID 8142622
 
Cytologic characterization and significance of normal karyotypes in t(8;21) acute myeloblastic leukemia.
Berger R, Bernheim A, Daniel MT, Valensi F, Sigaux F, Flandrin G
Blood. 1982 ; 59 (1) : 171-178.
PMID 6947830
 
The 8;21 chromosome translocation in acute myeloid leukemia is always detectable by molecular analysis using AML1.
Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y
Blood. 1993 ; 81 (6) : 1573-1579.
PMID 8453103
 
Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Franˆßais de Cytogˆ©nˆ©tique Hˆ©matologique.
Cancer genetics and cytogenetics. 1990 ; 44 (2) : 169-179.
PMID 2297675
 
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Contributor(s)

Written09-1997Jean-Loup Huret

Citation

This paper should be referenced as such :
Huret JL
t(8;21)(q22;q22) RUNX1/RUNX1T1;
Atlas Genet Cytogenet Oncol Haematol. September 1997
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Anomalies/t0821.html

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indexed on : Sat Jul 26 14:18:43 CEST 2014


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