A remarkABL new fusion oncogene in T-cell ALL

From www.bloodjournal.org by guest on December 17, 2014. For personal use only. of Gaucher disease and as-yet unknown ge- netic risk factors for the development of gam- mopathies in some patients. The difficulties in determining the genetic and mechanistic bases for this association highlight the complexities of this “simple” Mendelian disorder. ■ 2. Sidransky E. Gaucher disease and parkinsonism. Mol Genet Metab. 2005;84:302-304. 3. Shiran A, Brenner B, Laor A, Tatarsky I. Increased risk of cancer in patients with Gaucher disease. Cancer. 1993;72: REFERENCES 4. Allen MJ, Myer BJ, Khokher AM, Rushton N, Cox TM. Pro-inflammatory cytokines and the pathogenesis of Gaucher disease: increased release of interleukin-6 and in- terleukin-10. QJM. 1997;90:19-25. 1. Elstein D, Klutstein MW, Lahad A, Abrahamov A, Ha- das-Halpern I, Zimran A. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet. 5. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applica- tions. Blood. 2004;104:607-618. ● ● ● NEOPLASIA Comment on De Keersmaecker et al, page 4849 A remarkABL new fusion oncogene in T-cell ALL Richard A. Van Etten TUFTS-NEW ENGLAND MEDICAL CENTER A novel fusion of ABL1 to EML1 adds to a growing list of chimeric ABL proteins in patients with acute T-cell lymphoblastic leukemia. ntil recently, our recognition of the in- volvement of the ABL1 gene (which en- codes the nonreceptor protein tyrosine kinase c-ABL1) in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) was limited to rare cases of Philadelphia chromosome– positive T-ALL, some of which likely repre- sented lymphoid blast crisis of chronic my- eloid leukemia. The first hint that ABL1 might be involved more frequently in this disease came from a United Kingdom Medical Re- search Council study that used fluorescent in situ hybridization (FISH) with probes from the ABL1 locus to analyze interphase nuclei from lymphoid leukemia blasts. The study was intended to detect cryptic BCR-ABL1 fusion but instead found extrachromosomal amplifi- cation of the ABL1 locus independent of BCR in 8 of 280 T-ALL samples. 1 The nature of the amplification was soon revealed when re- searchers from the University of Leuven in Belgium demonstrated that ABL1 was fused to NUP214 via episomal amplification in 5 of 90 patients with T-ALL. 2 This resulted in fusion of N-terminal sequences of the NUP214 protein, a ubiquitously expressed component of the nuclear pore complex, with the same 1104 C-terminal amino acids of c- ABL1 found in the BCR-ABL1 fusion pro- tein. Like BCR-ABL1, the NUP214-ABL fusion is a constitutively active tyrosine kinase U blood 1 5 J U N E 2 0 0 5 I V O L U M E 1 0 5 , N U M B E R 1 2 related kinase (ERK), signal transducers and activators of transcription 5 (Stat5), and Src sig- naling pathways. As with BCR-ABL1, EML1- ABL kinase activity was dependent on a coiled- coil domain in the N-terminus, suggesting that oligomerization and autophosphorylation are necessary to overcome the autoinhibition of the ABL kinase domain. 3 The leukemic cells from this patient exhibited ectopic expression of the homeobox transcription factor TLX1 and hemizygous deletion of the CDKN2A tumor suppressor gene. These alterations were also seen frequently in patients with NUP214- ABL1 fusion 2 and provide more evidence that T-ALL can be divided into subgroups with distinct molecular pathogenesis. 4 Interest- ingly, expression of EML1 was not observed in other T-ALL blasts or cell lines, suggesting that the EML1 promoter may be activated as a consequence of the translocation. These findings have therapeutic implica- tions, of course. The EML1-ABL1 fusion pro- tein was inhibited by imatinib mesylate, the small molecule inhibitor of ABL kinase activity, with approximately the same sensitivity as BCR- ABL1, raising the possibility that patients with T-ALL with NUP214-ABL1 and EML1- ABL1 might respond clinically to imatinib treat- ment. In the previous study, imatinib was found to inhibit the growth of a T-ALL cell line with the NUP214-ABL1 fusion, 2 but the clinical util- ity of imatinib in these patients might be limited by rapid selection for resistance, as is observed in Philadelphia chromosome–positive patients with with transforming activity in vitro. Collec- tively, these results suggested that ABL1 might be involved in the pathogenesis of 5% to 6% of T-ALLs. In the current issue of Blood, the Leuven group extends these results to identify a new ABL1 fusion gene in T-ALL. A patient with T-ALL whose blasts lacked ABL1 amplification but demonstrated a split in the hybridization signal between 5⬘ and 3⬘ ABL1 probes was found to have cryptic t(9;14), leading to fusion of ABL1 with EML1 on chromosome 14. EML1 encodes a protein with similarity to an echino- derm microtubule-asso- ciated protein (EML1), and the resulting 190- kDa echinoderm micro- tubule-associated pro- tein–like 1–Abelson 1 (EML1-ABL1) fusion is a dysregulated ty- rosine kinase that allevi- ates interleukin-3 de- In T-ALL with cryptic t(9;14), N-terminal sequences from the EML1 polypeptide, pendence in Ba/F3 including a coiled-coil domain, are joined to the same C-terminal ABL se- hematopoietic cells and quences present in the more common BCR-ABL1 fusion protein. The resulting constitutively activates 190-kDa EML1-ABL1 fusion protein is a dysregulated tyrosine kinase that extracellular signal- transforms Ba/F3 cells. For details, see the article beginning on page 4849.