t - cell prolymphocytic leukemia ( t - pll ) is a rare type of peripheral t - cell leukemia with a naive t - cell phenotype . the clinical features of t - pll include marked hepatosplenomegaly and generalized lymphadenopathy with rapidly progressive lymphocytosis . the prognosis is generally poor due to resistance to chemotherapy , with a median survival ranging from 7.5 to 50 months [ 13 ] . chromosomal abnormalities such as t(14;14)(q11;q32 ) , inv(14)(q11;q32 ) and t(x;14)(q28;q11 ) have been identified in patients with t - pll , which result in the rearrangement of the tcl1 or mtcp1 genes with the t - cell receptor loci , which were thought to contribute to the pathogenesis of t - pll . we herein report a case of t - pll with a novel abl1 fusion gene which was fused to sept9 , sept9-abl1 . the case exhibited strong resistance to the tyrosine kinase inhibitors ( tki ) used against bcr - abl1 . this is the first report of t - pll with an abl1 fusion gene , and additionally , only the second report of a hematological malignancy with an abl1 fusion gene that exhibited a poor response to tki . a 70-year - old male was admitted to our hospital due to leukocytosis . on a physical examination , lymphadenopathy extending from the bilateral cervical to supraclavicular regions with moderate hepatomegaly was noted . the laboratory data on admission were as follows : white blood cells ( wbc ) , 24810/l with 0% neutrophils , 1% lymphocytes , 1% monocytes , 0% eosinophils , 0% basophils and 98% atypical lymphocytes , which were medium - sized with pale cytoplasm and prominent nucleoli ( fig . 1a ) ; red blood cells ( rbc ) , 411010/l ; hemoglobin ( hb ) , 12.4  g / dl ; and platelets ( plt ) , 17110/l . blood biochemistry was normal , except for elevated levels of lactate dehydrogenase and hepatobiliary enzymes . bone marrow aspirate smears showed marked proliferation of atypical lymphocytes with a similar morphology to that of the peripheral blood cells . using a cytogenetic analysis , a flow cytometric analysis showed that the atypical lymphocytes were positive for cd2 , cd4 , cd5 and cd7 . a bcr - abl fish analysis showed no bcr - abl signals , although 79 of 100 bone marrow cells exhibited atypical signals ( abl1 : three copies and bcr : two copies in each cell ) ( fig . the three abl1 signals indicated either simple amplification of the abl1 gene or the presence of abl1 rearrangement . in order to examine these two possibilities , the 5-terminal sequence of the abl1 gene was analyzed using the 5 race pcr method ( smarter race cdna amplification kit , takara bio , shiga , japan ) , according to the manufacturers protocol . sequencing of the pcr products demonstrated the fusion of exon 4 of sept9 to exon 2 of abl1 ( fig . 1c ) , suggesting that the sept9-abl1 fusion gene had the same breakpoint in abl1 as that seen in bcr - abl1 . 1d . a western blot analysis revealed the expression and phosphorylation of sept9-abl1 , in addition to the phosphorylation of a downstream target crkl , in the t - pll cells obtained from the patient ( fig . taking into account the patients clinical , morphological , immunophenotypic and molecular features , he was diagnosed with t - pll harboring sept9-abl1 . this is the first report of a novel sept9-abl1 fusion gene in a patient with malignancy , as well as t - pll harboring abl1 fusion . the patient received multiagent chemotherapy using cyclophosphamide , daunorubicin , vincristine , predonisolone and l - asparaginase , and high dose mtx / ara - c , as well as the single - agent administration of nelarabine , hydroxyurea and tyrosine kinase inhibitors ( tkis ) ( imatinib and dasatinib ) . the conventional chemotherapies and cytotoxic agents effectively reduced the wbc count , however , tkis were unable to do so . an autopsy was performed , and a macroscopic examination showed generalized lymphadenopathy with an enlarged lung , liver , spleen and kidney , while a microscopic examination disclosed leukemic cell infiltration throughout multiple organs ( fig . these findings suggested the occurrence of multiple organ failure due to a progression of leukemia which eventually caused the patients death . abl1 is a well - known oncogene that is often associated with the formation of fusion genes , such as bcr - abl1 , in human leukemia . the wild - type abl1 product transduces diverse extracellular signals to protein networks that control proliferation , survival , migration and invasion . additionally , abl1 modulates development and cytoskeletal remodeling processes in t - cells . to date , nine genes , including bcr , have been shown to fuse to abl1 
 . these genes are divided into two groups according to their structure : one group has a breakpoint in exon 2 including the src homology ( sh ) 2 and sh3 domains in the fusion products and is found in various kinds of leukemia , while the other has a breakpoint in exon 4 excluding these domains and is primarily found in patients with b - lymphoblastic leukemia ( b - all ) . both groups share the c - terminus structure , including the sh1 tyrosine kinase domain . the n - terminal of the fusion proteins usually includes a coiled - coil or helix - loop - helix domain from the partner protein , which induces the oligomerization of the proteins , thus resulting in tyrosine kinase activation , cytoskeletal localization and neoplastic transformation . sept9 plays a role in many cellular mechanisms , such as actin dynamics , axon growth , determination of the cell shape , chromosome segregation , cytokinesis , dendrite formation , dna repair , membrane trafficking , microtubule regulation and t - cell motility . furthermore , sept9 is deeply associated with the development of various cancers ( breast , colon , head , ovarian , neck , leukemia , lymphoma ) . in particular , it has been shown that sept9 is a putative proto - oncogene involved in t - cell lymphomagenesis in mice . in patients with hematological malignancies , mll ( kmt2a)-septin fusion has been repeatedly identified in cells exhibiting myeloid neoplasia in both children and adults . five different septin genes ( sept2 , sept5 , sept6 , sept9 and sept11 ) have been identified to be mll fusion partners . the c - terminal coiled - coil region of septin proteins is preserved in all mll - septin fusion products , thus indicating that this region contributes to protein in contrast , the n - terminal of sept9 is fused to abl1 in the sept9-abl1 fusion product . it includes the pro - rich region , which is necessary for binding with sh 3 regions . because the sh3 domain of abl1 is preserved in sept9-abl1 , this pro - rich region may contribute to an enhanced chimeric abl1 kinase potential by promoting interaction with abl1 sh3 regions , thereby synergistically inducing leukemogenesis . regarding the effectiveness of tkis , some , but not all , patients carrying the nup214-abl1 or etv6-abl1 fusion gene respond to such therapy . a recent report showed that b - all with snx2-abl1 responds poorly to dasatinib but partially to imatinib . in the present case these findings indicate that the tki response in patients with hematological malignancies associated with various abl1 fusion products is dependent on the abl1-partner genes . further examinations , including conformational analyses of abl1 fusion products , such as sept9-abl1 , and genetic alteration screening of abl1 fusion - expressing cells , will provide clues uncovering the mechanisms for determining sensitivity to tki therapy in patients with hematological malignancies harboring abl1 fusion products . r.s . performed the experiments , analyzed the data and prepared the manuscript ; hir.m . designed the experiments , performed the experiments , analyzed the data and prepared the manuscript ; hid.k . performed the experiments and analyzed the data ; k.a . designed the experiments , analyzed the data and prepared the manuscript .
t - cell prolymphocytic leukemia ( t - pll ) , a rare type of peripheral t - cell leukemia , is characterized by marked splenomegaly with rapidly progressive lymphocytosis and a poor prognosis . 
 nine kinds of abl1 chimeric genes have been identified in various kinds of hematological malignancies , such as chronic myeloid leukemia and b- or t - lymphoblastic leukemia . however , there have been no reports describing t - pll cases with abl1 rearrangements . 
 we herein report a case of t - pll with a novel sept9-abl1 fusion gene which induced strong resistance to tyrosine kinase inhibitors such as imatinib and dasatinib .