• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • The patient received multiagent chemotherapy using cyclophos


    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. He finally died on day 223 after diagnosis (Fig. 2A). 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. 2B). These findings suggested the occurrence of multiple organ failure due to a progression of leukemia which eventually caused the patient׳s death.
    Discussion 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 [4]. Additionally, ABL1 modulates development and cytoskeletal remodeling processes in T-cells. To date, nine genes, including BCR, have been shown to fuse to ABL1[5]. These genes are divided into two groups according to their structure: one group has a breakpoint in 69 8 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 [5]. Septin proteins belong to a family of proteins that is highly conserved in eukaryotes [6]. These proteins are GTP-binding proteins that form hetero-oligomeric complexes. There are 13 septin genes in humans [6]. The SEPT9 gene exists at chromosomal location 17q25 and exhibits a ubiquitous expression. 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 [6]. Furthermore, SEPT9 is deeply associated with the development of various cancers (breast, colon, head, ovarian, neck, leukemia, lymphoma) [6]. In particular, it has been shown that SEPT9 is a putative proto-oncogene involved in T-cell lymphomagenesis in mice [7]. 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 [8]. 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–protein interactions and ultimately oncogenesis. 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 [9]. 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 [5]. A recent report showed that B-ALL with SNX2-ABL1 responds poorly to dasatinib but partially to imatinib [10,11]. In the present case, SEPT9-ABL1 exhibited a strong resistance to both imatinib and dasatinib. We confirmed that there were no point mutations in the SEPT9-ABL1 fusion gene. 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.