Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.

Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia.

Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia.

Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients.

Rosai-Dorfman disease with lung involvement in a 10-year-old patient: A case report.

Background: Rosai-Dorfman disease (RDD) is a rare benign proliferative disease whose etiology is not clear and may be related to infection or unexplained immune dysfunction. The authors present a case of RDD with lung involvement in a 10-year-old patient.

Case Summary: A 10-year-old girl found that her left cervical lymph nodes were enlarged for more than 7 mo, and the largest range was about 6.

An aging mouse model of human chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival.

Laryngopharyngeal reflux disease management for recurrent laryngeal contact granuloma: A case report.

Background: Laryngeal contact granuloma (LCG) is difficult to treat and frequently associated with high persistence and recurrence, despite the availability of both surgical and pharmacological treatment options. An appropriate strategy is therefore needed to help patients with multiple recurrences of LCG to potentially avoid unnecess-ary surgery.

Case Summary: We describe the case of a 34-year-old male patient with recurrent LCG in which a good response was achieved through successful management of laryngophar-yngeal reflux disease using a combination pharmacotherapeutic regimen consisting of anti-reflux therapy, pepsin secretion inhibition, bile acid neutralization, and lifestyle modifications.

PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells.

The fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies.

An emerging trend of rapid increase of leukemia but not all cancers in the aging population in the United States.

The "baby boomers" born in 1946-1964 in the United States (U.S.) started to reach the age of 65 in 2011, rapidly accelerating U.

A Convenient Cell Culture Model for CML Acquired Resistance Through BCR-ABL Mutations.

Tyrosine kinase inhibitors (TKIs) are the effective treatments for chronic myeloid leukemia (CML). However, clinical resistance to TKIs that leads to patient relapse remains a challenge. Acquisition of BCR-ABL mutations is crucial in the resistance but the underlying molecular mechanisms are poorly understood.

SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells.

Acquisition of BCR-ABL mutations underlies drug resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors, but the molecular mechanisms of mutation acquisition are poorly understood. We previously showed that lysine deacetylase sirtuin 1, SIRT1, promotes acquisition of BCR-ABL mutations in association with enhancing KU70 mediated non-homologous end joining DNA repair. In this study, we demonstrate that lysine specific demethylase 1 (LSD1) plays an opposite role to SIRT1 in regulating DNA repair and mutation acquisition.

CD150(-) Side Population Defines Leukemia Stem Cells in a BALB/c Mouse Model of CML and Is Depleted by Genetic Loss of SIRT1.

Leukemia stem cells (LSCs) of chronic myeloid leukemia (CML) are refractory to tyrosine kinase inhibitor treatment, persist in the residual disease, and are important source for disease recurrence. Better understanding CML LSCs will help devise new strategies to eradicate these cells. The BALB/c mouse model of CML using retroviral bone marrow transduction and transplantation is a widely used mouse model system for CML, but LSCs in this model are poorly characterized.

ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance.

Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes.

The emerging and diverse roles of sirtuins in cancer: a clinical perspective.

Sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein lysine modifying enzymes with deacetylase, adenosine diphosphateribosyltransferase and other deacylase activities. Mammals have seven sirtuins, namely SIRT1-7. They are key regulators for a wide variety of cellular and physiological processes such as cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development, aging, and cancer.

Roles of SIRT1 in leukemogenesis.

Purpose Of Review: This review provides a concise summary of significant research progress on SIRT1 deacetylase in leukemia in the past year. SIRT1 is a multifunctional protein and recent studies demonstrate that SIRT1 plays a crucial role in myeloid leukemogenesis and drug resistance.

Recent Findings: SIRT1 expression is typically low in normal adult hematopoietic stem/progenitor cells, but is increased in the leukemic stem/progenitor cells of chronic myeloid leukemia (CML).

Sirtuins in hematological aging and malignancy.

Aging of the hematological system causes anemia, reduced immunity, and increased incidence of hematological malignancies. Hematopoietic stem cells (HSCs) play a crucial role in this process as their functions decline during aging. Sirtuins are a family of protein lysine modifying enzymes that have diverse roles in regulating metabolism, genome stability, cell proliferation, and survival, and have been implicated in mammalian aging and longevity.

Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining.

Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions.

Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib.

BCR-ABL tyrosine kinase inhibitors (TKI) fail to eliminate quiescent leukemia stem cells (LSC) in chronic myelogenous leukemia (CML). Thus, strategies targeting LSC are required to achieve cure. We show that the NAD(+)-dependent deacetylase SIRT1 is overexpressed in human CML LSC.

Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis.

The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but primary and acquired resistance of CML cells to the drug offset its efficacy. Molecular mechanisms for resistance of CML to tyrosine kinase inhibitors are not fully understood. In the present study, we show that BCR-ABL activates the expression of the mammalian stress response gene SIRT1 in hematopoietic progenitor cells and that this involves STAT5 signaling.

Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model.

Serine/threonine kinase Aurora A is essential for regulating mammalian cell division and is overexpressed in many types of human cancer. However, the role of Aurora A in chemoresistance of chronic myelogenous leukemia (CML) is not well understood. Using the KCL-22 cell culture model we have recently developed for studying mechanisms of CML acquired resistance, we found that Aurora A expression was partially reduced in these cells upon treatment with the tyrosine kinase inhibitor imatinib, which accompanied the acquisition of BCR-ABL mutation for imatinib resistance.

BCR-ABL gene expression is required for its mutations in a novel KCL-22 cell culture model for acquired resistance of chronic myelogenous leukemia.

Acquired resistance through genetic mutations is a common phenomenon in several cancer therapies using molecularly targeted drugs, best exemplified by the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia (CML). Overcoming acquired resistance is a daunting therapeutic challenge, and little is known about how these mutations evolve. To facilitate understanding the resistance mechanisms, we developed a novel culture model for CML acquired resistance in which the CML cell line KCL-22, following initial response to imatinib, develops resistant T315I BCR-ABL mutation.

[Clinical observation on acupuncture kinetotherapy for acute simple laryngitis of wind-heat type].

Objective: To observe clinical therapeutic effect of acupuncture kinetotherapy for acute simple laryngitis of wind-heat type and to probe the mechanism.

Methods: Eighty cases were randomly divided into a test group and a control group, 40 cases in each group. The test group were treated with acupuncture kinetotherapy (Acupuncture was given at Kaiyin point No.

Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.

Hypermethylated in cancer 1 (HIC1) is an epigenetically regulated transcriptional repressor that functionally cooperates with p53 to suppress age-dependent development of cancer in mice. Here we show that the mechanism by which the loss of HIC1 function promotes tumorigenesis is via activating the stress-controlling protein SIRT1 and thereby attenuating p53 function. HIC1 forms a transcriptional repression complex with SIRT1 deacetylase, and this complex directly binds the SIRT1 promoter and represses its transcription.

Inactivation of tumor suppressor genes: choice between genetic and epigenetic routes.

Inactivation of tumor suppressor genes can occur via epigenetic or genetic mechanisms. The reasons underlying this choice of gene inactivation routes during tumorigenesis have not been clarified, nor have the precise roles in cancer evolution for genes which are solely affected by epigenetically mediated loss of function. Here we discuss a mouse model in which the disruption of Hic1, a gene solely involved with epigenetic silencing in human cancer, can markedly influence the disruption of the powerful tumor suppressor gene, p53, in determining malignant tumor incidence, spectrum and virulence.

Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors.

The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor that belongs to a group of proteins known as the POZ family. HIC1 is hypermethylated and transcriptionally silent in several types of human cancer. Homozygous disruption of Hic1 impairs development and results in embryonic and perinatal lethality in mice.