Prospective isolation of hematopoietic stem and progenitor cells has identified the lineal relationships among all blood-cell types and has allowed their developmental mechanisms to be assayed at the ...single-cell level. These isolated cell populations are used to elucidate the molecular mechanism of lineage fate decision and of its plasticity directly by stage-specific enforcement or repression of lineage-instructive signaling in purified cells. With an emphasis on the myeloid lineage, this review summarizes current concepts and controversies regarding adult murine hematopoietic development and discusses the potential mechanisms, operated by single or by multiple transcription factors, of myeloid lineage fate decision.
Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic ...intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias.
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•TIM-3+ AML LSCs secrete its ligand galectin-9 in an autocrine manner•TIM-3/galectin-9 autocrine signaling co-activates NF-κB and β-catenin in LSCs•This signaling is commonly used by LSCs in most myeloid malignancies
Signaling mechanisms specifically active in leukemic stem cells (LSCs) provide therapeutic opportunities. Akashi and colleagues identify a TIM-3/Gal-9 autocrine stimulatory loop that regulates self-renewal of human LSCs, through co-activation of NF-κB and β-catenin signaling, and promotes leukemic progression in a range of myeloid malignancies.
Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Here we identified T cell immunoglobulin mucin-3 (TIM-3) as a surface ...molecule expressed on LSCs in most types of AML except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). TIM-3
+ but not TIM-3
− AML cells reconstituted human AML in immunodeficient mice, suggesting that the TIM-3
+ population contains most, if not all, of functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden and eliminated LSCs capable of reconstituting human AML in secondary recipients. These data suggest that TIM-3 is one of the promising targets to eradicate AML LSCs.
► TIM-3 is highly expressed in stem cells in AML of most FAB types except for M3 ► TIM-3 is not expressed in normal hematopoietic stem cells ► TIM-3 killing antibody treatment could eradicate human AML in a xenograft model ► Targeting TIM-3 could be a practical approach for human AML treatment
Therapeutic plasma exchange (TPE) is a strategy for treating cold agglutinin disease (CAD) in order to manage hemolytic complications. However, there are no reports of hemolysis during TPE. A ...41-year-old man with secondary CAD was unable to undergo initial TPE because of red blood cell agglutination and hemolysis in his extracorporeal circulation. To avoid low temperatures, the patient and extracorporeal circulation were kept warm by covering and heating them, and finally, he was able to successfully receive TPE three times. Although our approach still has room for improvement, our management protocol appears to be an effective treatment modality for such cases.
Hereditary angioedema (HAE) is a life-threatening disease associated with recurrent episodes of subcutaneous and mucosal swelling, painful abdominal cramping, and asphyxiation. HAE has long been ...thought to be caused by genetic defects of C1 inhibitors (C1-INH). Recently, HAE with a normal C1 inhibitor expression (HAEnCI) was reported, and the missense mutation p.Lys330Glu (K330E) in exon 9 of the plasminogen (PLG) gene was shown to be responsible for a subset of HAEnCI. HAE with the K330E mutation in the PLG gene-PLG (HAE-PLG) has been reported in only two Japanese families in Asia. We herein report a third family with HAE-PLG in Japan.
We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients ...with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors.
► HSCs in CLL have cell-intrinsic propensity to generate clonal CLL-like B cells ► Abnormal karyotypes are not required for appearance of such B cell clones ► The majority of single HSCs in patients with CLL display lymphoid-lineage priming ► HSCs can be involved in oncogenesis even in mature lymphoid tumors
Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment‐refractory (R/R) AML or newly diagnosed patients with ...poor prognostic factors. Alvocidib (DSP‐2033), a potent cyclin‐dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open‐label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30‐min intravenous (i.v.) bolus (30 mg/m2/d), followed by a continuous i.v. infusion over 4 h on days 1–3 (60 mg/m2/d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose‐limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.
The data demonstrated that both alvocidib regimens had an acceptable safety profile in Japanese patients with AML. The clinical activity was also promising, although this was a very small group of patients.
Acute lymphoblastic leukemia (ALL) is a common neoplasm in children, but less frequent in adults. Since information on clinical features and genetics of adult ALL in Japan is limited, we analyzed 215 ...subjects aged 16–65 years with untreated ALL enrolled in the Fukuoka Blood & Marrow Transplant Group studies ALL MRD 2002 and 2008. The prevalence of ALL was bimodal, with the larger group aged 56–65 years. Immunophenotypic characterization showed B-lineage is more frequent than T-lineage ALL (78.6 vs 13.0%), with age-related differences. The proportion with
BCR-ABL1
rearrangement increased progressively with age, up to 55.7% among subjects aged over 56–65 years. Rearrangements involving the
KMT2A
gene,
ETV6-RUNX1
, and
TCF3-PBX1
were rare in this study cohort. The overall incidence of hyperdiploidy was only 1.7%, and there were no cases with hypodiploidy. Overall survival varied by age and cytogenetics. Older subjects and those with
BCR-ABL1
tended to have inferior outcomes. In this epidemiological study of Japanese adult ALL, the majority of subjects had B-lineage ALL, the T-cell phenotype was most frequent in those aged 16–25, and
BCR-ABL1
rearrangement was very common, with prevalence increasing with age. These types of adult ALL are potentially manageable with targeted therapies.
CD28, one of the costimulatory molecules, has a pivotal role in T‐cell activation, and its expression is strictly regulated in normal T cells. Gain‐of‐function genetic alterations involving CD28 have ...been frequently observed in adult T‐cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non‐overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86‐positive non‐neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non‐overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.
The aim of the present study was to determine the clinicopathological significance of CD28 overexpression in adult T‐cell leukemia/lymphoma (ATLL). CD28 overexpression is associated with unfavorable prognosis of ATLL patients who were treated with multidrug regimens including mogamulizumab; thus, CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL.
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