Acute basophilic leukemiat(X;6)(p11;q23) MYB/GATA1

2012-06-01   Cathy Quelen 

1.Institut National de la Sante et de la Recherche Medicale, U1037, Centre de Recherche sur le Cancer de Toulouse, Toulouse, France
2.Genetique des Hemopathies, Laboratoire dHematologie, Hopital Purpan, 31059 Toulouse Cedex, France

Clinics and Pathology

Disease

Rare type of acute myeloid leukemia (AML)

Phenotype stem cell origin

Basophilic precursor.

Epidemiology

Very rare but might be prominent in infants. Four cases of acute basophilic leukemia with t(X;6)(p11;q23) translocation occurring in male infants (< 1 year) have been described.

Clinics

Hyperhistaminemia syndrome has been reported in some of the cases.
Atlas Image
Cytology of blast cells. A: Presence of basophilic granules in the cytoplasm of leukemic cells after May Grünwald Giemsa staining. B: Positive reaction for toluidine blue cytochemistry.

Cytology

Major component of undifferentiated blasts and minor component of basophilic blasts containing large granules reacting positively to toluidine blue staining.

Treatment

AML protocols. All patients received standard therapy for childhood AML; Two out of 4 cases reported underwent intrafamilial hematopoietic stem cell transplantation.

Evolution

The 4 patients are still in complete remission, with the following follow-ups: 24 years (P1), 18 years (P2 allografted), 4 years (P3) and 14 years (P4 allografted).

Prognosis

Good response to standard therapy for childhood AML.

Note

One patient had a K-RAS exon 2 mutation (G12S).

Cytogenetics

Atlas Image
Karyotype of patients at the diagnosis (Patient 1: G-banding; Patient 2 and 3: R-banding). For Patient 3, the chromosome 12 is involved in the rearrangement.

Cytogenetics morphological

t(X;6)(p11;q23)

Cytogenetics molecular

Molecular cytogenetics (FISH) revealed unbalanced and more complex rearrangements than those observed on karyotype:
PatientKaryotype at diagnosis /
Karyotype revised after FISH analysis (BACs, Fosmids and mBAND)
P146,Y,t(X;6)(p11;q23)[40]/46,XY[1]
der(X)(6qter→6q24::6q23::Xp11→Xq13::6q22q23::Xp11→Xp22::Xq24::Xp22→Xpter), der(6)(6pter→6q22::Xq28→ Xq25::Xq23→ Xq13::Xqter)
P246,Y,t(X;6)(p11;q23)[29]/46,XY[1]
no material available
P346,Y,der(X)t(X;12)(p21;q23)t(X;6)(q28;q23), der(6)t(X;6)(q28;q23), del(12)(q23)[18]/46,XY[6]
der(X)(12qter→12q23::6q22→6q23::Xp11→Xq28::Xp11→Xpter), del(6)(q21q23),del(12)(q23)
P446,Y,t(X;6)(p11;q23)[16]/46,XY[13]
der(X)(6qter→6q24::6q23::Xp11→Xq23::Xq25→Xqter), der(6)(6pter→6q23::Xp11→Xp21::Xq24::Xp21→Xpter)
Atlas Image
RP11-104D9 (Red) and RP11-905P20 (Green) span the 5 part of MYB and the 3 part of MYB respectively. RP11-104D9 is delocalized onto der(X).

Genes Involved and Proteins

Gene name
MYB (v-myb myeloblastosis viral oncogene homolog (avian))
Location
6q23.3
Protein description
MYB is a transcription factor composed of three domains: an N-terminal DNA binding domain composed of three imperfect repetitions forming a helix-turn-helix structure, a central transactivation domain and a C-terminal negative regulatory domain. MYB is a master regulator of haematopoiesis involving in proliferation, survival and differentiation of hematopoietic cells.
Gene name
GATA1 (GATA binding protein 1 (globin transcription factor1))
Location
Xp11.23
Protein description
GATA1 is a transcription factor composed of an N-terminal activation domain and two zinc-finger domains. GATA1 play an essential role in erythroid differentiation.

Result of the Chromosomal Anomaly

Note

The t(X;6)(p11;q23) resulted in MYB-GATA1 fusion gene.

Description

5MYB-3GATA1. Breakpoint occurred in the intron 8-9 of MYB and in the intron 4-5 of GATA1.

Transcript

The fusion transcript fused the 5 part of MYB up to exon 8 to the 3 part of GATA1 from exon 5 to the end. This translocation is associated with loss of expression of wild type GATA1 in leukemic cell due to the involvement of the chromosome X carrying GATA1.
Atlas Image
Schematic representation of MYB, GATA1 and MYB-GATA1 proteins. MYB is composed of R1, R2 and R3 which are three imperfect repeats that encompass the DNA-binding domain (DBD) of MYB. TAD is the transactivation domain of MYB and NRD is the negative regulatory domain. GATA1 is composed of an activation domain (AD) and two zinc finger domains. MYB-GATA1 keeps both the DBD and the minimal TAD of MYB and the c-terminal zinc finger domain of GATA1. The breakpoint at the amino acid level is indicated by the blue arrow.

Description

The predicted fusion protein comprises the DNA binding domain and the minimal transactivation domain of MYB fused to the DNA binding domain of GATA1.

Expression localisation

MYB-GATA1 is expressed in the nucleus.

Oncogenesis

Expression of MYB-GATA1 in mouse hematopoietic progenitors committed them to the granulocyte lineage, blocked them at an early stage of differentiation and transformed these cells.

Bibliography

Pubmed IDLast YearTitleAuthors
92335811997Acute basophilic leukaemia and translocation t(X;6)(p11;q23).Dastugue N et al
214746712011Identification of a transforming MYB-GATA1 fusion gene in acute basophilic leukemia: a new entity in male infants.Quelen C et al

Summary

Fusion gene

MYB/GATA1 MYB (6q23.3) GATA1 (Xp11.23) M t(X;6)(p11;q23)|MYB/GATA1 MYB (6q23.3) GATA1 (Xp11.23) TIC

Citation

Cathy Quelen

Acute basophilic leukemiat(X;6)(p11;q23) MYB/GATA1

Atlas Genet Cytogenet Oncol Haematol. 2012-06-01

Online version: http://atlasgeneticsoncology.org/haematological/1124/acute-basophilic-leukemiat(x;6)(p11;q23)

Historical Card

1998-02-01 Acute basophilic leukemiat(X;6)(p11;q23) MYB/GATA1 by  Nicole Dastugue 

Genetique des Hemopathies, Laboratoire dHematologie, Hopital Purpan, 31059 Toulouse Cedex, France

External Links