The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic ...syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia.
Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma characterized by production of the immunoglobulin M (IgM) monoclonal protein. Commonly involved sites are the bone marrow, lymph nodes, ...and spleen. Lymphoplasmacytic infiltration of the central nervous system (CNS), in contrast, is referred to as Bing–Neel syndrome, and is an extremely rare phenomenon. Here, we present a unique case of Waldenström macroglobulinemia with optic neuritis accompanied by monoclonal expansion of T cells, which recovered after administration of CNS-targeting chemotherapy. Although the underlying causal relationships in this case remain obscure, aberrantly expanded T cells may have contributed to the development of optic neuritis, and we should be reminded that some types of cranial neuropathy in Waldenström macroglobulinemia may be reversible.
Levofloxacin is widely used as antimicrobial prophylaxis against high-risk chemotherapy-induced neutropenia. Garenoxacin, a fluoroquinolone developed in Japan, shows a stronger in vitro antimicrobial ...activity against Gram-positive bacteria than levofloxacin.
We retrospectively analyzed high-risk patients with acute myeloid leukemia who were administered garenoxacin (n = 36) or levofloxacin (n = 120) during chemotherapy. We compared the profiles of infections between these fluoroquinolones.
Febrile events occurred in 31 (86%) and 93 (78%) cases in the garenoxacin and levofloxacin group, respectively (P = 0.35). Bloodstream infections by Gram-positive bacteria were recorded in one (3%) case in the garenoxacin group and 25 (21%) cases in the levofloxacin group (P < 0.01). In contrast, bloodstream infections by Gram-negative microorganisms were identified in five (4%) cases in the levofloxacin group and eight (22%) cases in the garenoxacin group (P < 0.01).
These results indicate that there may be substantial differences in the antimicrobial spectrum between different fluoroquinolones. Although there are several biases due to rather small sample size and the retrospective nature, we should take the differences into consideration when we administer a prophylactic fluoroquinolone to a patient with hematological disease.
The QuantiFERON-TB Gold In-Tube
®
test has excellent specificity for
Mycobacterium tuberculosis
. However, diagnosis of miliary tuberculosis remains challenging, and the interpretation of QuantiFERON
...®
results in immunocompromised individuals has not been fully established. Here, we present a patient with military tuberculosis who showed an indeterminate QuantiFERON
®
result. A 76-year-old male presented with fever and pancytopenia. Radiological tests did not show the classical miliary pattern. Acid-fast staining and polymerase chain reaction of several specimens were negative for
M. tuberculosis
. The QuantiFERON
®
responses were indeterminate on two separate tests, as interferon-γ (IFN-γ) concentration was high in the negative control. The patient did not respond to anti-microbiological therapy, and developed sepsis and disseminated intravascular coagulation, leading to lethal intracranial hemorrhage. An autopsy showed miliary tuberculosis and aplastic anemia. A literature review suggests a tendency towards indeterminate or false-negative QuantiFERON
®
results in immunocompromised individuals or patients with miliary tuberculosis due to low production of IFN-γ. Our patient, however, showed substantial amounts of IFN-γ despite lymphocytopenia, which has not been reported in the literature. The present case suggests that indeterminate results of QuantiFERON
®
should be interpreted with caution, as IFN-γ production in patients with miliary tuberculosis can vary significantly, even with sustained lymphocytopenia.
Targeting mRNA Decapping in AML Yoshimi, Akihide; Abdel-Wahab, Omar
Cancer cell,
03/2018, Letnik:
33, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous ...aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.
Spliceosomal mutations, especially mutations in
SF3B1
, are frequently (>80%) identified in patients with refractory anemia with ringed sideroblasts (RARS) and myelodysplastic/myeloproliferative ...neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T; previously known as RARS-T), and
SF3B1
mutations have a high positive predictive value for disease phenotype with ringed sideroblasts. These observations suggest that
SF3B1
mutations play important roles in the pathogenesis of these disorders and formation of ringed sideroblasts. Here we will review recent insights into the molecular mechanisms of mis-splicing caused by mutant
SF3B1
and the pathogenesis of RSs in the context of congenital sideroblastic anemia as well as RARS with
SF3B1
mutations. We will also discuss therapy of
SF3B1
mutant MDS, including novel approaches.
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will ...be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
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