Despite substantial advances in anti-myeloma treatments, early recurrence and death remain an issue in certain subpopulations. Cytogenetic abnormalities (CAs) are the most widely accepted predictors for poor prognosis in multiple myeloma (MM), such as t(4;14), t(14;16), t(14;20), gain/amp(1q21), del(1p), and del(17p). Co-existing high-risk CAs (HRCAs) tend to be associated with an even worse prognosis. Achievement of sustained minimal residual disease (MRD)-negativity has recently emerged as a surrogate for longer survival, regardless of cytogenetic risk. Information from newer clinical trials suggests that extended intensified treatment can help achieve MRD-negativity in patients with HRCAs, which may lead to improved outcomes. Therapy should be considered to include a 3- or 4-drug induction regimen (PI/IMiD/Dex or PI/IMiD/Dex/anti-CD38 antibody), auto-transplantation, and consolidation/maintenance with lenalidomide ± a PI. Results from ongoing clinical trials for enriched high-risk populations will reveal the precise efficacy of the investigated regimens. Genetic abnormalities of MM cells are intrinsic critical factors determining tumor characteristics, which reflect the natural course and drug sensitivity of the disease. This paper reviews the clinicopathological features of genomic abnormalities related to adverse prognosis, focusing on HRCAs that are the most relevant in clinical practice, and outline current optimal therapeutic approaches for newly diagnosed MM with HRCAs.

Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

Background: Like normal hematopoietic stem cells, leukemia cells proliferate in bone marrow, where oxygen supply is limited. However, the growth and energy metabolism of leukemia cells under hypoxia have not been well understood. Although it has been known that reactive oxygen species (ROS) is generated under hypoxic conditions, normal and leukemia stem cells were characterized by relatively low levels of ROS. Roles of ROS on leukemia cells under hypoxia also have not been well understood. Methods: Four Leukemia cell lines were cultured under normoxia (21% O₂) or hypoxia (1% O₂), where NB4 and THP-1 were most extensively studied. To evaluate energy metabolism, we estimated whole cell number or apoptotic cells with or without a glycolysis inhibitor or an oxidative phosphorylation (OXPHOS) inhibitor. Glucose consumption and lactate production were also measured. To evaluate oxidative stress in hypoxic condition, the ROS level and GSH (reduced glutathione) / GSSG (oxidized glutathione) ratio was measured. In addition, pyruvate dehydrogenase kinase 1 (PDK1) and cytochrome c oxidase subunit 4 (COX4) were examined by western blotting or RT-PCR. Results: NB4, which grows well under normoxia depending on glycolysis, demonstrated prominent apoptosis and growth suppression after 48 hours culture under hypoxia. NB4 cells cultured under hypoxia showed significantly increased ROS. Culture with a ROS scavenger resulted in decrease of apoptotic cell death of NB4 under hypoxia. NB4 cells cultured for longer period (7 days) under hypoxia did not come to extinction, but grew slowly by upregulating GSH synthesis to protect from ROS generated in hypoxic condition. By contrast, THP-1, which largely depends on OXPHOS in mitochondria under normoxia, demonstrated more growth under hypoxia by changing metabolism from OXPHOS to glycolysis through upregulating PDK1. Moreover, THP-1 avoided ROS generation by substituting COX 4 subunit (from COX 4–1 to COX 4–2) through upregulation of LON, a mitochondrial protease under hypoxia. Conclusions: We showed that leukemia cells survive and adapt to the hypoxic condition through various pathways. Our results will help understanding energy metabolism of leukemia cells and creating novel therapeutics.

Gnetin-C is a naturally occurring stilbene derived from the seeds of Gnetum gnemon L., an edible plant native to Southeast Asia that is called melinjo. Although the biological properties and safety of G. gnemon extract, which contains nearly 3% Gnetin-C, have been confirmed in various human studies, whether or not pure Gnetin-C is safe for humans is unclear at present. We conducted a randomized, double-blind, placebo-controlled trial. Healthy subjects were randomly divided into two groups. The interventional group (n = 6) was given Gnetin-C, and the control group (n = 6) was provided a placebo, for 14 days. Lipid profiles, biomarkers of oxidative stress and circulating blood cells were assessed before and after the intervention. All subjects completed the study, with no side effects reported across the study duration. Gnetin-C supplementation demonstrated a statistically significant increase in the absolute number of circulating natural killer (NK) cells expressing the activating receptors NKG2D and NKp46. NK cells derived from subjects who received Gnetin-C for two weeks showed higher cytotoxicity against K562 target cells than those before receiving Gnetin-C. In addition, Gnetin-C also resulted in a significant decrease in the absolute neutrophil count in the blood compared with the placebo. Furthermore, Gnetin-C significantly reduced the levels of uric acid, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total adiponectin, and high-molecular-weight adiponectin. These data indicate that Gnetin-C has biological effects of enhancing the NK activity on circulating human immune cells. The immunomodulatory effects are consistent with a putative improvement in cancer immunosurveillance via the upregulation of the NKG2D receptor. The study was registered with UMIN-CTR, number 000030364, on 12 December 2017.

Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS‐11, OCI‐My5, and ANBL‐6), we generated FAM46C^−/− cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C^−/− KMS‐11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C^−/− cell‐derived tumors than mice with the FAM46C^WT cell‐derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C^−/− cells compared to WT cells. In addition, caspase activities decreased in the FAM46C^−/− cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum‐responsive genes while inactivating phosphatase and tensin homolog (PTEN)‐related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF‐04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C^−/− MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K‐Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene.

Internal tandem duplication (ITD) ofFMS-like tyrosine kinase 3(FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboringFLT3-ITD, the therapeutic effect is limited. Here, to explore alternative therapeutics, we established a cellular model of monoallelicFLT3^ITD/WTcells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevatedCD52expression in K562–FLT3^ITD/WTcells compared to K562–FLT3^WT/WTcells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression ofCD52in K562–FLT3^ITD/WTcells was decreased in wild-typeFLT3(FLT3-WT) knock-in K562–FLT3^ITD/WTcells. In K562–FLT3^ITD/WTcells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Notably, an anti-CD52 antibody, alemtuzumab, induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) in K562-FLT3^ITD/WTcells compared to K562–FLT3^WT/WTcells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562–FLT3^ITD/WTcells in severe combined immunodeficiency (SCID) mice. Taken together, our data suggested that genetically modifiedFLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562–FLT3^ITD/WTcells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with theFLT3-ITD mutation.