Leukemogenesis of b2a2-type p210 BCR/ABL in a Bone Marrow Transplantation Mouse Model Using a Lentiviral Vector

Uchida, Naoya; Hanawa, Hideki; Dan, Kazuo; Inokuchi, Koiti; Shimada, Takashi

doi:10.1272/jnms.76.134

Cited by 19 publications

(20 citation statements)

References 28 publications

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“…This difference in frequencies may possibly be due to the genetic background of the populations. Moreover, it was found that CML patients at diagnosis expressed low e1a2 transcript frequency, besides the usual BCR-ABL1 p210 [14,15] or only 5% [16], or no co-expression whatsoever in previous Iranian study [8]. In this study, co-expression of p210 and p190 in 5%, which is closed to Mexican study, was detected [16].…”

Section: Discussioncontrasting

confidence: 49%

The Frequency of BCR-ABL1 Fusion Transcripts in Iranian Patients with Three Different Types of Leukemia

Hamid

Bokharaei

2017

Zahedan J Res Med Sci

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Background: Different BCR-ABL fusion transcripts occur more or less frequently, in three different types of leukemia Objectives: This study was done to determine the frequencies of BCR-ABL fusion transcripts in leukemia patients from Iran. Methods: This experimental study was carried out from 2001 to 2015 in Pasteur Institute of Iran. The leukemia patients containing 348 chronic myeloid leukemia (CML), 72 acute lymphoblastic leukemia (ALL), and 34 acute myeloid leukemia (AML) were studied. Total RNA was extracted from peripheral blood samples and analyzed by multiplex RT-PCR in 486 leukemia patients to detect different types of BCR-ABL transcripts. Fisher's exact test was used in comparing qualitative variables in the case control study. Associations with a P value < 0.05 were considered significant. Results: The BCR-ABL transcript frequencies for CML, ALL and AML patients were 92.0%, 12.5% and 14.7% respectively for all transcripts. The majority of CML patients with positive BCR-ABL expressed one of the p210 BCR-ABL transcripts (86.6%) while the remaining showed

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Section: Discussioncontrasting

confidence: 49%

The Frequency of BCR-ABL1 Fusion Transcripts in Iranian Patients with Three Different Types of Leukemia

Hamid

Bokharaei

2017

Zahedan J Res Med Sci

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“…Lentiviral titers (transduction units/ml) were calculated by the proportion of GFP-positive cells (%GFP) using a HeLa cell line, as previously described [12, 14]. This viral titer was used to calculate MOI for both HeLa and CD34 + cells.…”

Section: Methodsmentioning

confidence: 99%

“…Human immunodeficiency virus type 1 (HIV-1) based lentiviral vectors were pursued for efficient transduction for HSCs and long-term gene expression in vivo due to the ability of HIV-1 vectors to transduce non-dividing cells and integrate into host cell chromosomes [9–11]. However, even when using HIV-1 vectors, transduction efficiency for human HSCs is less than various cell lines and mouse HSCs [12–14]. Generally, HIV-1 vectors can transduce almost 100% of cells in various cell lines (including HeLa cells), while around 10–40% of transduction efficiency is achieved among human CD34 + cells, even at high multiplicity of infection (MOI) [14].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of lentiviral vector transduction in human CD34+ cells

Uchida

Green

Ballantine

et al. 2016

Experimental Hematology

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Unlike cell lines, human hematopoietic stem cells (HSCs) are less efficiently transduced with HIV-1 vectors, potentially limiting this approach. To investigate which step (internalization, reverse transcription, nuclear transport, and integration) limits lentiviral transduction, we evaluated the kinetics of lentiviral transduction in human CD34+ cells. We transduced HeLa and CD34+ cells with self-inactivating HIV-1 vector at low and 10-fold higher MOIs, and evaluated vector amounts at various timepoints based upon the rationale that if a given step was not limiting, 10-fold greater vector amounts would be obtained at the 10-fold higher MOI. We observed slower internalization (>60 minutes), a peak of reverse transcription at 24 hours, and completion of integration at 3 days in CD34+ cells. In HeLa cells, vector amounts at high MOI achieved ~10-fold greater values over all timepoints. When compared to HeLa cells, CD34+ cells had a larger difference of vector amounts between high and low MOIs at 2–6 hours and a smaller difference at 12 hours to 10 days, revealing a limitation in human CD34+ cell transduction around 12 hours, which corresponds to reverse transcription. In serial measurements of reverse transcription at 24 hours, vector amounts didn’t decrease once detected among CD34+ cells. When using an HSC expansion medium, we observed less limitation for starting reverse transcription and more efficient transduction among CD34+ cells in vitro and in xenografted mice. These data suggest that initiation of reverse transcription mainly limits lentiviral transduction for human CD34+ cells. Our findings provide an avenue for optimizing human CD34+ cell transduction.

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“…Although the initial intention of this study was to model CML, expression of p210 via a myeloproliferative sarcoma virus (MPSV) in BM cells from BALB/c led not only to CML, but B and T ALL and macrophage derived tumor in 13 of 30 mice studied (48). A follow-up report using the same p210 BCR-ABL protein (b3a2) in BALB/c BM transduction/transplant studies, compared another p210 BCR-ABL protein (b2a2), resulting from an alternative breakpoint, when driven by a murine stem cell virus (MSCV) U3 promoter found that both gave rise to B ALL without any evidence of myeloid leukemia (49). Yet another group utilized a MPSV system to express p210 BCR-ABL in mouse BM and also observed a broad range of diseases in two different mouse strains (50).…”

Section: B Cell All Modelsmentioning

confidence: 99%

Murine Models of Acute Leukemia: Important Tools in Current Pediatric Leukemia Research

2014

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Leukemia remains the most common diagnosis in pediatric oncology and, despite dramatic progress in upfront therapy, is also the most common cause of cancer-related death in children. Much of the initial improvement in outcomes for acute lymphoblastic leukemia (ALL) was due to identification of cytotoxic agents that are active against leukemia followed by the recognition that combination of these cytotoxic agents and prolonged therapy are essential for cure. Recent data demonstrating lack of progress in patients for whom standard chemotherapy fails suggests that the ability to improve outcome for these children will not be dramatically impacted through more intensive or newer cytotoxic agents. Thus, much of the recent research focus has been in the area of improving our understanding of the genetics and the biology of leukemia. Although in vitro studies remain critical, given the complexity of a living system and the increasing recognition of the contribution of leukemia extrinsic factors such as the bone marrow microenvironment, in vivo models have provided important insights. The murine systems that are used can be broadly categorized into syngeneic models in which a murine leukemia can be studied in immunologically intact hosts and xenograft models where human leukemias are studied in highly immunocompromised murine hosts. Both of these systems have limitations such that neither can be used exclusively to study all aspects of leukemia biology and therapeutics for humans. This review will describe the various ALL model systems that have been developed as well as discuss the advantages and disadvantages inherent to these systems that make each particularly suitable for specific types of studies.

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Leukemogenesis of b2a2-type p210 BCR/ABL in a Bone Marrow Transplantation Mouse Model Using a Lentiviral Vector

Cited by 19 publications

References 28 publications

The Frequency of BCR-ABL1 Fusion Transcripts in Iranian Patients with Three Different Types of Leukemia

The Frequency of BCR-ABL1 Fusion Transcripts in Iranian Patients with Three Different Types of Leukemia

Kinetics of lentiviral vector transduction in human CD34+ cells

Murine Models of Acute Leukemia: Important Tools in Current Pediatric Leukemia Research

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