Gene Map Locus: 5q35
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Large-cell lymphomas comprise approximately 25% of all non-Hodgkin lymphomas
in children and young adults. Approximately one-third of these tumors have a
t(2;5)(p23;q35) chromosomal translocation, which suggests that rearrangement of
cellular protooncogenes on these chromosomes contributes to lymphomagenesis. To
clone the genes altered by the t(2;5), Morris
et al. (1994) used a positional strategy based on fluorescence in situ
hybridization (FISH) ordering of regionally derived cosmid clones. Bidirectional
chromosome walks were performed from cosmids approximately 290 kb apart that
flanked the breakpoint on chromosome 5; each walk spanned a genomic region of
150 kb. In this way, they showed that the rearrangement fused the NPM nucleolar
phosphoprotein gene on 5q35 to a previously unidentified protein tyrosine kinase
gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the N-terminus
of nucleophosmin was found to be linked to the catalytic domain of anaplastic
lymphoma kinase (ALK; 105590).
Expressed in the small intestine, testis, and brain but not in normal lymphoid
cells, ALK shows greatest sequence similarity to the insulin receptor subfamily
of kinases. Unscheduled expression of the truncated ALK may contribute to
malignant transformation in these lymphomas. FISH mapping indicated that the NPM
and ALK genes are transcribed in centromere-to-telomere orientations on
chromosome 5 and 2, respectively, with the 2.4-kb transcript arising from the
derivative 5 translocated chromosome. Northern blot analysis provided no
evidence for expression of a reciprocal ALK-NPM chimeric transcript.
Acute promyelocytic leukemia (APL) is uniquely associated with chromosomal
translocations that disrupt the gene encoding the retinoic acid receptor, RARA
(180240).
In more than 99% of cases, this disruption results from the formation of a
PML-RARA fusion gene through translocation. Rare variants of APL have been
described, in which RARA is fused to 1 of 3 other genes, PLZF (176797),
NUMA (164009),
and NPM (Redner
et al., 1996).
Cheng
et al. (1999) generated transgenic mice with Plzf-Rara and Npm-Rara.
Plzf-Rara transgenic animals developed chronic myeloid leukemia-like phenotypes
at an early stage in life (within 3 months in 5 of 6 mice), whereas 3 Npm-Rara
transgenic mice showed a spectrum of phenotypes from typical APL to chronic
myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to
bone marrow cells from Plzf-Rara transgenic mice, those from Npm-Rara transgenic
mice could be induced to differentiate by all-trans-retinoic acid (ATRA). Cheng
et al. (1999) found that in interacting with nuclear coreceptors the 2
fusion proteins had different ligand sensitivities, which may be the underlying
molecular mechanism for differential responses to ATRA. These data clearly
established the leukemogenic role of PLZF-RARA and NPM-RARA and the importance
of fusion receptor/corepressor interactions in the pathogenesis as well as in
determining different clinical phenotypes of APL.