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Inside this Issue: November and December

Posted By Connections Editor, Wednesday, December 16, 2015



Newly identified mutations contributing to leukemogenesis and therapy resistance in AML
See Sykes et al., pages 989

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Unfortunately, even with aggressive treatment, including high-dose chemotherapy and bone marrow transplantation, most patients relapse and develop resistance to anti-leukemic therapies, resulting in 5-year overall survival rates between 30% and 40%. Increasing evidence supports a model for leukemia evolution whereby mutations accumulate in functionally normal hematopoietic stem cells during a prolonged “preleukemic” phase. Recent advances in whole-genome sequencing and global genomic approaches have provided a long list of newly identified mutations. However, even with these advances, how these molecular abnormalities contribute to the etiology, pathogenesis, and therapeutic responses of AML remains largely unknown. The International Society of Experimental Hematology invited Dr. Ross L. Levine and Dr. Ravindra Majeti, two authorities on AML, to conduct a webinar (available online at presenting their most recent research on this topic. In this perspective, Sykes et al. summarize the key points discussed in both presentations, which centered on the most recent published data concerning the pathogenesis of AML, including, but not limited to, clonal evolution, newly identified mutations in AML patients, and mutational cooperativity. In addition, they discuss the clinical and basic research implications of their work, as well as novel therapies that are currently emerging in AML treatment.


Multiple roads to genomic instability in Fanconi anemia
See Abdul-Sater et al. pages 1031

Inherited mutations within FANCA or other FA genes cause Fanconi anemia (FA), a bone marrow failure syndrome associated with myelodysplasia (MDS) and acute myeloid leukemia (AML). Acquired FA mutations drive AML in patients without FA. The FA pathway orchestrates both interphase DNA repair and mitosis; thus, FA mutations may unleash genomic instability via multiple mechanisms. However, the in vivo impact of interphase and mitotic errors on FA−/− hematopoiesis is unknown. To address this issue, Abdul-Sater et al. employed in this study a battery of quantitative assays and discovered increased frequency of abnormal mitoses during in vivo hematopoiesis in non-leukemic FANCA−/− patients and Fancc−/− mice, suggesting that these mitotic errors may ultimately cause leukemia. Mechanistically, live FANCA−/− cells failed to efficiently assemble mitotic spindles. Superresolution microscopy revealed that FANCA shuttles from centrioles to microtubule- attachment sites at the centrosome periphery in early mitosis, possibly to fine-tune microtubule nucleation.
In accordance with FA genes acting as mitotic housekeepers, loss of FANCA or FANCC rendered cells hypersensitive to antimitotic chemotherapeutics. Importantly, the authors illustrate that functionally different chemotherapeutics selectively damage FA−/− cells through distinct mechanisms. Although crosslinking drugs shatter DNA and activate the G2/M cell cycle checkpoint, low-dose antimitotic chemotherapy amplifies chromosome segregation errors. Accordingly, loss of FA signaling promotes genomic instability through complementary interphase and mitotic defects. Together, these findings not only provide insights into the complex mechanisms of genomic instability resulting from loss of the FANCA tumor suppressor, but also suggest that precision medicine therapeutics targeting erroneous mitosis may selectively kill FANCA−/− leukemia and other cancers.


VEGF may not be the most suitable target for anti-angiogenic therapy in primary myelofibrosis
See Dragoni et al., pages 1019

Increased angiogenesis is a major histopathologic feature of both bone marrow and spleen of patients with primary myelofibrosis (PMF). This has prompted the design of therapeutic protocols based on the use of anti-angiogenic drugs directed mainly against vascular endothelial growth factor (VEGF), the major regulator of such a process. However, despite the strong rationale for the use of anti-VEGF treatments, these trials have resulted in poor outcomes. In the recent past, it has been proposed that circulating endothelial progenitor cells have a role in angiogenesis in different diseases, including PMF. Dragoni et al. report that PMF patient-derived endothelial colony-forming cells, the only bona fide endothelial progenitor cells described so far, mount a defective proangiogenic response to VEGF in vitro, assessed in terms of Ca2+ oscillations, proliferation, and tubulogenesis. Importantly, this reported alteration in VEGF-mediated calcium flux in these endothelial colony-forming cells was previously unrecognized. These results, in addition to the previous report from the same group of an increased frequency of these cells in the peripheral blood of PMF patients, open new perspectives on the potential role of circulating endothelial progenitor cells in the pathogenesis of PMF. In particular, these data shed new light on the failure of anti-VEGF therapy in PMF patients and represent valuable information for the design and development of new anti-angiogenic drugs for the cure of this disease.


Innate and adaptive immune response: Help for curing CML?
See Caocci et al., pages 1015
Withdrawal of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) continues to be a much debated issue, and the search for clinical and/or biological patterns predictive of stable molecular remission (MR) and, perhaps, even definitive recovery is still underway. In a previous article, this group reported that homozygosity for killer cell immunoglobin-like receptor (KIR) A haplotype was significantly associated with achievement of deep MR. In this article, Caocci et al. report that after discontinuation of TKIs, MR was significantly higher in patients homozygous for KIR A haplotype and/or carrying specific combinations of KIRs and their HLA class I ligands. Although the study cohort is quite small and a bit heterogeneous, this article provides interesting novel findings on a hot topic in current CML treatment and suggests that natural killer cells and their KIRs cooperate with TKIs in the cure of CML.
There are many reasons why both physicians and their patients prefer to stop therapy. Some worth mentioning are the high cost, adverse events, poor compliance, the desire for pregnancy, and treatment-related poor quality of life. Ongoing clinical trials investigating TKI discontinuation should soon release more details on the safety of stopping treatment and the ideal candidates for this option. Meanwhile, on the basis of this and other studies, the important function of both innate and adaptive immune responses in controlling CML should be given attention. Further appreciation of immune regulation is a fundamental step toward improved treatment approaches and the development of anti-inhibitory KIR antibodies or vaccination strategies.





Reduced dose of cyclophosphamide post-HLA haploidentical peripheral blood stem cell transplantation as an option for high-risk leukemia and MDS patients
See Nakamae et al., pages 921–929

Nonmyeloablated T-cell–replete HLA haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide (PT/Cy) has shown encouraging outcomes with low transplantation-related mortality. High-dose Cy is capable of controlling graft versus host disease (GVHD) and preventing graft rejection; however, the high relapse rate remains a major issue of concern, particularly with high-risk hematological malignancies. In this prospective pilot study, Nakamae et al. investigate two reduced dosages of PT/Cy for patients with a poor prognosis, refractory leukemia, or myelodysplastic syndrome. The authors report a trend toward a lower incidence of severe acute GVHD at day 100 in the “25 mg/kg × 2 doses of PT/Cy” group compared with the “25 mg/kg of PT/Cy” group. Although they use peripheral blood as a stem cell source for all patients, the cumulative incidence of chronic GVHD was very low in both groups. BK virus hemorrhagic cystitis occurred more frequently in the double-dose PT/Cy group, particularly when busulfan was used for conditioning. The probability of overall survival at 1 year in the double dose group was better than that in the single dose group despite the absence of statistical significance. Overall, these results suggest that HLA haploidentical T-cell–replete peripheral blood stem cell transplantation with 25 mg/kg × 2 doses of PT/Cy might be a feasible option for high-risk leukemia and MDS patients. It thus might be worthwhile to compare the efficacy of a double dose of 25 mg/kg PT/Cy with the original PT/Cy double dose of 50 mg/kg in a large prospective study.


Osteoblast stimulating factor-5 (OSF-5); a novel tuner in B lymphopoiesis
See Fujita et al., pages 963–973

B lymphocytes are developed from hematopoietic stem cells (HSC) in their specialized microenvironment. In contrast to the recent progress in understanding the HSC niche, the mechanisms regulating the B lymphopoietic niche have remained unclear. To shed light on this issue, Fujita et al. identify several molecules secreted by the B lymphopoietic niche using signal sequence trap. First, the authors examined the proteins produced by MS5 stromal cells, which are B lymphopoiesis supportive cells commonly used in models of in vitro B lymphopoiesis. They identified pleiotrophin, placental proliferin-2, and osteoblast stimulating factor-5 (OSF-5). On the basis of experiments with transgenic mice and in vitro studies, they found that a secreted variant of OSF-5 inhibits proliferation at the pre–B cell stage. Furthermore, the authors show that human mesenchymal cells also express OSF-5 and, as in mice, this molecule suppresses the proliferation of human pre–B cells. These results identify OSF-5 as a new negative regulator of B lymphopoiesis and provide a framework to identify molecules that can be used to speed the regeneration of the humoral immune system after chemotherapy, and potentially suggesting ways to inhibit the growth of B lineage malignancies.


New biomarkers of AML dynamics
See Tzoran et al., pages 936–943

Acute myeloid leukemia (AML) is characterized by rapid growth of leukemic blasts. Cell exposure to chemo- or radiotherapy increases the shedding into the blood circulation of extracellular vesicles (EVs), which express antigens reflecting their cellular origin. Despite normalization of blood counts, AML patients in remission still harbor leukemic burden. This fact emphasizes the need to develop diagnostic tools capable of identifying minimal residual disease (MRD). The current study by Tzoran et al. explores the role of circulating EVs as potential biomarkers of AML activity and predictors of thrombogenicity in patients who are reported to be at increased risk for thrombotic events. The authors demonstrate that circulating EVs of AML patients express leukemic blast membrane proteins, with their levels significantly varying at diagnosis, nadir, and remission, thus reflecting the disease dynamics. Blast EV counts were found to be higher in patients at diagnosis compared with healthy controls. In remission, a statistically significant correlation between the percentage of CD117-labelled EVs in the peripheral blood and the amount of CD117-positive blasts in the bone marrow was revealed. Moreover, blast EV levels at remission were significantly lower in patients who were alive at 3 years of follow-up compared with those who succumbed to the disease, indicating the high predictive value of this biomarker. Additionally, EV procoagulant activity was increased in patients compared with controls and induced high endothelial cell thrombogenicity. This study provides a platform for the use of EVs as potential biomarkers of minimal residual disease and the procoagulant state in AML patients.


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