t(11;17)(q13;q21)

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t(11;17)(q13;q21)

Clinics and Pathology

Disease	atypical M3 ANLL (in most cases, M3 ANLL is characterized by a t(15;17)(q25;q21))
Epidemiology	exceptional (only 1 case fully described), a 6 mth old male patient
Clinics	multiple cutaneous localizations; blue-green macules on the scalp and the trunk; coagulation parameters and platelets count were normal
Prognosis	complet remission obtained with ATRA treatment and autologous bone marrow transplantation (38 mths disease-free follow up after BMT)

Cytogenetics

Additional anomalies

Variants

3 related translocations observed in M3 ANLL; the first is the common translocation (15;17) and the two others are extremelly rare; all these translocations involve a breakpoint at 17q21, in RARa, which fuses with different partners: 1- t(15;17)(q22;q21), fusion with PML in 15q22; 2- t(5;17)(q32;q12), fusion with NPM1 in 5q32, encoding for a RNA processing protein; 3- t(11;17)(q23;q21), fusion with PLZF in 11q23, a transcription factor.

Genes involved and Proteins

Gene Name	NuMA
Location	11q13
Protein	NuMA protein is an essential component for the formation and maintenance of mitotic spindle poles during mitosis; dimerization domain and nuclear localisation signal.

Gene Name	RARa
Location	17q12-21
Protein	wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation.

Result of the chromosomal anomaly

Hybrid gene

Description	fusion gene on der(11) encompassed by a lamba phage clone B350g; breakpoint in RARa gene in the usual breakpoint cluster region within intron 2.
Transcript	5' NuMA - 3' RARa transcript; no reciprocal 5' RARa - 3' NuMA transcript can be detected

Fusion Protein

Description	2284 amino acids, 260 kDa; includes the NH2-terminal globular domain and the alpha helical dimerization domain of NuMA (amino acids 1 to 1883) linked to the ligand-binding, dimerization and DNA-binding domains of RARa (amino acids 61 to 462)
Expression Localisation	nuclear localisation, under the form of sheet-like nuclear aggregates which partially co-localizes with normal NuMA protein
Oncogenesis	as for the three other translocations associated with APL, the main consequence of NuMA-RARa fusion seems to be an alteration in the retinoid signalling pathway; as for PML, PLZF or NPM, NuMA, the forth fusion partner of RARa would " share the capacity to participate in protein-protein interactions, which may result in the formation of abnormal heterodimers or aggregates in which co-activators of retinoid signalling are sequestered "

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