T-cell acute lymphoblastic leukemia (T-ALL)

Not seen in B-cell ALL or other malignant diseases. , The main hypothesis is that genomic amplification is a dynamic process. Molecular chronology of genomic amplification has been schematically described as follows. The first step is the production of submicroscopic, acentric, circular, extrachromosomal DNA molecules which replicate autonomously, called episomes. These DNA molecules are made of amplified genes. 2 mechanisms for the formation of episomes have been proposed: Conservative which preserves the original DNA sequence at the native chromosomal locus and non conservative which leads to the deletion of the original sequence at the native locus. The second step corresponds to an increase in copy number resulting from unequal mitotic segregation and an increase in size. They enlarge over time to form progressively heterogeneously sized structures, microscopically visible, called double minutes (dmin). In a later step they may integrate into chromosomes to generate intrachromosomally amplified structures (HSR). In some cases dmins or HSRs may form directly without precursors.

Immature T-cell leukemia (CD3+, CD2+ and CD7+).

In about 5% of T-ALL. Mainly observed in T-ALL associated with the mutually exclusive overexpression of the oncogenes HOX11 and HOX11L2. Found in pediatric and adults T-ALL.

No major clinical differences between NUP214-ABL negative and positive T-ALL.

Lymphoblasts.

NUP214-ABL1 cells are sensitive to tyrosine kinase inhibitors (ITK). Targeting therapies may improve outcome of patients with T-ALL expressing NUP214-ABL1 but the clinical experience is, yet, too limited to conclude.

Most data, but not all, suggests that NUP214-ABL1 fusion gene amplification in T-ALL is associated with poor outcome.

Mechanism of gene amplification

Not detectable by conventional cytogenetics. Cryptic, no dmin.

FISH using commercially available ABL1 probe shows multiple extrachromosomal sites on metaphases and multiple signals in interphase nuclei. The extrachromosomal amplification of ABL1 appears to be pathognomonique for the presence of NUP214-ABL1 fusion in T-ALL.There may be a corresponding deletion of the ABL1 probe on one of the chromosomes 9 (see note above concerning mechanisms of gene amplification).

ABL1 probe.

None. In apparently normal karyotype or with variable additional abnormalities.

NUP214 is recognized as being the second most prevalent fusion gene involving ABL1.

Molecular analyses delineated the amplicon as a 500 kb region from chromosome band 9q34 containing the genes ABL1, LAMC3 and NUP214. The genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion gene = New mechanism for generation of a fusion gene. The breakpoint within ABL1 occurs in intron 1 in most cases, in intron 2 in other cases (coincides with ABL1 breakpoint in the Philadelphia chromosome). Whilst the breakpoint in NUP214 is variable (ranging from intron 23 to intron 34).

NUP214-ABL1 fusion gene.

RT-PCR of the fusion transcript.

The NUP214-ABL transcript encodes a 239-333 kDa protein which includes the coiled-coil domain (dimerisation motifs necessary for tyrosine kinase activation and neoplastic transformation) of NUP214 and the tyrosine kinase domain of ABL1.

NUP214-ABL protein is a constitutively activated tyrosine kinase most likely implicated in the pathogenesis of T-ALL in a similar mechanism of action as for BCR-ABL as it activates similar pathways and for its sensitivity to ITK. However NUP214-ABL protein is less potent and requires amplification for neoplastic transformation.

NUP214 is also involved in the translocation t(6;9) seen in myeloid malignancies which results in the fusion gene DEK-NUP214. Unlike NUP214-ABL where the N-terminal region of NUP214 is retained, in DEK-NUP214, it is the C-terminal region of NUP214 which is present. The mode of leukemogenesis of DEK-NUP214 is thought to be interference with nucleocytoplasmic transport processes. It is unknown whether NUP214-ABL acts in the same way.

Episomes are submicroscopic extrachromosomal structures.