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Inside the March & April Issues

Posted By Connections Editor , Thursday, May 1, 2014
Updated: Wednesday, April 30, 2014
See Syrjänen et al., pages 230–240.

The role of the Trans-membrane (or T cell) immunoglobulin and mucin (TIM) family members in the adult immune system involves the regulation of Th cell responses and removal of apoptotic bodies through phosphatidylserine. However, their expression and role during the development of immune cells is undetermined. To address this, Syrjänen et al. analyzed TIM expression in chicken and mouse hematopoiesis. The most striking finding of the study is the clear restriction of tim-4 expression to fetal liver and especially to fetal liver CD45+F4/80+ cells. Furthermore, two distinct TIM-4+ populations were seen: F4/80hiTIM-4hi and F4/80loTIM-4lo. The authors showthat the F4/80hiTIM-4hi cells had the morphology of mature macrophages and had no in vitro hematopoietic potential, suggesting that they are functional macrophages. On the other hand, F4/80loTIM-4lo cells expressed stem cell markers and had multi-lineage myeloid potential. In addition, the F4/80loTIM-4lo cells included a considerable population
expressing ER-MP12, a known marker for macrophage-colony forming cells and other myeloid progenitors. Therefore, the authors suggest that TIM-4 is a marker for myeloid progenitors. In the future, TIM-4 could be utilized in the isolation or characterization of myeloid progenitor cells. It will also be intriguing to find out whether TIM-4 has a functional role in cell differentiation. 

See Beaudin et al., pages 218–229.

Defining the role of the tyrosine kinase receptor Flk2/Flt3 in hematopoietic differentiation is critical for understanding how aberrant Flk2 activity promotes acute myeloid leukemia. Previous studies focused on the prominent role of Flk2 in lymphoid differentiation suggested that Flk2 regulates cell fate by biasing progenitors toward a lymphoid fate at the expense of megakaryocyte/erythroid potential, but this model fails to explain how activating mutations in Flk2 promote myeloid leukemias. In this issue, Beaudin et al. clarified the role of Flk2 in regulating myeloid development by investigating the effect of Flk2 deficiency on myeloid specification in vivo. Quantification and functional assessment of purified stem and progenitor
populations from Flk2-deficient mice revealed that Flk2 promotes both myeloid and lymphoid development. Furthermore, transplantation of equivalent numbers of WT and Flk2-deficient multipotent progenitors resulted in only a subtle lymphoid defect, indicating that Flk2 promotes the expansion of multipotent progenitor cells. Consistent with this concept, Flk2 deficiency impaired proliferation and cell cycle status of stem and progenitor cells, resulting in reduced sensitivity of Flk2-deficient mice to treatment with the myeloablative agent 5-fluorouracil.
Collectively, the findings by Beaudin et al. support a model in which Flk2 promotes the
expansion of multipotent progenitors that give rise to all myeloid and lymphoid lineages but does not instruct lineage choice. These data yield a fresh perspective regarding the function of Flk2 in normal hematopoiesis and provide new insights into how activating mutations in Flk2 promote leukemogenesis.

See Feng et al., pages 172–182.

The ubiquitin-proteasome system plays a fundamental role in cellular homeostasis. In general, cancer cells have higher levels of proteasome activity compared with normal cells, making this an ideal target for anti-cancer therapies. At present, the proteasome inhibitor bortezomib is used as a first-line therapy for multiple myeloma (MM). However, development of resistance to bortezomib is a major issue, and thus there is a need for the development of new drugs. The small molecule b-AP15 is a novel inhibitor of proteasome deubiquitination activity. Recent studies have shown that b-AP15 displays anti-tumor activity in several pre-clinical solid tumor models. In this study, Feng et al. found that b-AP15 triggers apoptosis of the human MM
cell lines, RPMI8226 and U266. The induction of apoptosis in MM cells was dependent on caspase activation and partially dependent on cathepsin D, a lysosomal protease. The authors further demonstrated that b-AP15 engages the mitochondrial apoptosis pathway in MM cells, as the drug triggered a significant loss of mitochondrial transmembrane potential as well as activation of the pro-apoptotic protein Bax. Notably, the latter effects were caspase independent. Finally, the authors noted that b-AP15 triggers caspase-independent apoptosis in natural killer (NK) cells. Notwithstanding, the study sheds new light on apoptosis induction by b-AP15 and supports the use of b-AP15 or related compounds for the treatment of MM, including in patients who develop resistance to conventional treatments.

See Iwamoto et al., pages 163–171.

Xenotransplantation models using immunodeficient mice are widely used for human stem cell assays. However, this model shows strain-specific differences in the engraftment, and nonobese diabetic (NOD) background strains are the most efficient. This group has previously shown that
the polymorphism of the signal regulatory protein-alpha (Sirpa), which inhibits phagocytic activity of macrophages through binding to its ligand CD47, determines the engraftment
and tolerance of xenotransplants in NOD-scid mice. The BALB/c strain of immunodeficient mice is another strain that can support human hematopoietic reconstitution in vivo. In the present study, Iwamoto et al. tested whether the efficient xenotransplantation capability of the BALB/c
strain is also mediated by the SIRPA-CD47 self-recognition system. The authors sequenced the IgV domain of mouse Sirpa, which contains the binding site of CD47, and compared the binding affinities of C57BL/6, BALB/c, and NOD SIRPA to human CD47. They found
that a BALB/c-specific polymorphism, L29V, confers moderate affinity for human CD47 to mouse SIRPA on the macrophage membrane, which inhibits macrophage-mediated elimination of the human hematopoietic cells. These findings further indicate that the mouse strain effect on xenotransplant efficiency might be explained by the binding affinity between strain-specific SIRPA and human CD47. This information is useful to establish a novel, more efficient immunodeficient mouse model for human cell transplantation by strengthening the binding between mouse SIRPA and human CD47. In addition, the data show that the SIRPA SNPs can influence the binding to CD47 and phagocytic activity, raising an interesting question of whether there might be SIRPA or CD47 SNPs that disrupt the SIRPA-CD47 self-recognition
system and induce human diseases.

Sadovnik et al., pages 282–293.
Chronic eosinophilic leukemia (CEL) is a neoplasm characterized by uncontrolled expansion of eosinophils with consecutive organ damage. In many patients, eosinophils express the FIP1L1-PDGFRA oncoprotein. This oncogenic mutant contributes essentially to factor-independent
growth and accumulation of eosinophils in CEL. The PDGFR kinase blocker imatinib is successfully used to suppress growth of neoplastic eosinophils in these patients. Notably, most CEL patients treated with imatinib enter continuous complete remission. However, not all patients with CEL show a long-lasting response to imatinib, but relapse after a certain time interval. For these patients, alternative drugs have to be considered, especially when secondary mutations are detectable in FIP1L1-PDGFRA. In the present study, Sadovnik and colleagues
have examined the effects of various clinically relevant tyrosine kinase inhibitors on growth and survival of EOL-1 cells, a human CEL-related cell line exhibiting the FIP1L1 PDGFRA mutant. The data obtained show that several of the tyrosine kinase inhibitors tested, including ponatinib, sorafenib, masitinib, nilotinib, and dasatinib suppress growth and survival ofEOL-1 cells at a low nM range. In addition, these drugs were found to inhibit cytokine induced migration of eosinophils. However, only ponatinib was found to block the growth of Ba/F3 cells expressing the imatinib-resistant FIP1L1-PDGFRA mutants T674I and D842V. These observations may
have clinical implications. Indeed, based on the authors’ opinion, clinical trials are now warranted to explore the clinical potency of ponatinib in drug-resistant eosinophilic leukemias or other neoplasms expressing drug-resistant mutant forms of PDGFRs.

Visfatin (VF) is a newly discovered adipocytokine thought to play a role in the pathogenesis
of metabolic syndrome–related cancers. Originally identified as a pre B cell colony enhancing factor, it is found in different tissues and organs and performs many functions, including enhancing cell proliferation. The peptide acts as an enzyme, growth factor, and cytokine in
several processes including cell growth, cell survival, DNA replication, and repair.
Currently there are no data about the role of VF in pediatric leukemia and stem cell
transplantation. In this study, Skoczen et al report decrease in VF concentrations in 22
children with leukaemia referred to haematopoietic stem cell transplantation, and normalization of the peptide level after the procedure. It is suggested in the literature that VF is an important factor in carcinogenesis and a potential prognostic marker in several solid tumours. The presented findings suggest that decreased VF in leukaemic children in complete remission
may be caused by myelo- and immunosuppression after many cycles of chemotherapy. Because VF has antiapoptotic activity, reduced levels may result in increased antitumor activity, which may be beneficial for the patients. The authors speculate that the recovery of the plasma VF concentration after transplantation might be caused by a process of immune reconstitution or complications of the procedure, such as prolonged inflammation (infections or GvHD), injury to organs (lungs, gut, and liver), and endocrinology deficiencies. If these findings can be supported by studies with larger cohorts, VF could be an additional marker of leukaemia status and proper reconstitution of cell lineages after haematopoietic stem cell transplantation.

Ueno et al., pages 307–316.

Acute B-cell lymphoblastic leukemia (B-ALL) is the major type of ALL and it can occur at
any age. Despite a good prognosis in most pediatric B-ALL patients, the treatment for adult and
high risk pediatric B-ALL remains challenging. Therefore, exploring new targets or pathways
are essential for the development of better therapeutic options for these patients. SALL4 is an
embryonic stem cell factor which plays an essential role in the maintenance of embryonic stem cell properties. SALL4 is expressed during development, but downregulated and absent in most adult tissues. However, it is re-expressed in various cancers including B-ALL. In this study, Ueno et al. report that SALL4 was constitutively expressed in B-ALL and was a key survival factor for B-ALL cells. Downregulation of SALL4 in B-ALL cells led to decreased cell proliferation, increased apoptosis in vitro, and impaired leukemic engraftment in a xenotransplant model in vivo. SALL4 affected B-ALL cell survival through multiple caspase members. Furthermore, the authors reported that hypomethylation of the SALL4 CpG islands was correlated with its increased expression level. This is the first report to demonstrate that the aberrant expression of SALL4 in B-ALL is associated with hypomethylation, and that SALL4 plays a key role in B-ALL cell survival. The authors further propose that SALL4 could be a novel therapeutic target for B-ALL, and new treatment options such as targeting SALL4 could be developed in the future to treat B-ALL patients.

Jung et al., pages 274–281.

Cellular immunotherapy using dendritic cells (DCs) is emerging as a strategy to treat multiple
myeloma (MM); however, the clinical results have been unsuccessful. Attempts to improve
DC vaccination have included better cytokine combinations to enhance DC function, effective
tumor antigens to induce specific cytotoxic T lymphocytes, and the modification of signal transcriptions to overcome defective DC function. Immunosuppressive cytokine from MM cells,
including transforming growth factor beta, interleukin-10 (IL-10), IL-6, and vascular endothelial growth factor, can modulate host immune responses, including the abrogation ofDCfunction by the constitutive activation of the signal transducer and activator of transcription-3 (STAT-3). A recent study has reported that treating MM cells with the proteosome inhibitor bortezomib could increase the expression of heat-shock protein (HSP) 90 on the myeloma cell surface and
enhance the antitumor immunity against MM in DC-based immunotherapy. In this study, Jung et al. tested whether the synergistic action of bortezomib and JSI-124 (curcurbitacin-I, p-STAT3 inhibitor) could be used to generate highly potent tumor antigens to induce immunogenic death of tumor cell expressing HSPs. The combination treatment resulted in the highest expression of HSP90 and the lowest expression of p-STAT3 in dying myeloma cells. DCs loaded with treated dying myeloma cells recovered from the abnormal cytokine secretions of IL-10, IL-6, and IL-23 without any effect on production of IL-12p70. DCs loaded with JSI-124 and bortezomib-treated dying myeloma cells generated potent myeloma-specific cytotoxic T lymphocytes. This data suggest that pretreatment of myeloma cells with a combination of JSI- 124 and bortezomib can recover DC dysfunction upon loading with dying myeloma cells through the upregulation
of HSP90 and the downregulation of p-STAT3 and inhibitory cytokines. This strategic approach of combining two agents, which target two key survival pathways in the MM cells and neutralize their secretion of released mediators that render DC functions ineffective, is an important incremental step in the ongoing quest for the development of an immunotherapeutic approach to the treatment of MM.

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