miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

FAS promoter polymorphism: outcome of childhood acute myeloid leukemia. A children's oncology group report.

PURPOSE: FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down-regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine transition in the FAS promoter region (position -1377) is thought to reduce stimulatory protein 1 transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at -1,377 bp significantly attenuates transcription factor stimulatory protein 1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might affect outcome of childhood AML therapy. EXPERIMENTAL DESIGN: Four hundred forty-four children treated for de novo AML on a uniform protocol were genotyped for FAS 1377. RESULTS: There were no significant differences in overall survival, event-free survival, treatment-related mortality, or relapse rate between patients with FAS 1377GG genotype versus 1377GA/1377AA genotypes. CONCLUSIONS: FAS 1377 genotype does not alter outcome of de novo AML in children

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressing acute lymphoblastic leukemia

The Formulation of a Rapid Transit Plan for the Detroit Metropolitan Area: 1953-1958.

Ph.D.Public administrationUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/156725/1/6001787.pd

Increasing the efficiency of trial-patient matching: automated clinical trial eligibility Pre-screening for pediatric oncology patients

Background: Manual eligibility screening (ES) for a clinical trial typically requires a labor-intensive review of patient records that utilizes many resources. Leveraging state-of-the-art natural language processing (NLP) and information extraction (IE) technologies, we sought to improve the efficiency of physician decision-making in clinical trial enrollment. In order to markedly reduce the pool of potential candidates for staff screening, we developed an automated ES algorithm to identify patients who meet core eligibility characteristics of an oncology clinical trial. Methods: We collected narrative eligibility criteria from ClinicalTrials.gov for 55 clinical trials actively enrolling oncology patients in our institution between 12/01/2009 and 10/31/2011. In parallel, our ES algorithm extracted clinical and demographic information from the Electronic Health Record (EHR) data fields to represent profiles of all 215 oncology patients admitted to cancer treatment during the same period. The automated ES algorithm then matched the trial criteria with the patient profiles to identify potential trial-patient matches. Matching performance was validated on a reference set of 169 historical trial-patient enrollment decisions, and workload, precision, recall, negative predictive value (NPV) and specificity were calculated. Results: Without automation, an oncologist would need to review 163 patients per trial on average to replicate the historical patient enrollment for each trial. This workload is reduced by 85% to 24 patients when using automated ES (precision/recall/NPV/specificity: 12.6%/100.0%/100.0%/89.9%). Without automation, an oncologist would need to review 42 trials per patient on average to replicate the patient-trial matches that occur in the retrospective data set. With automated ES this workload is reduced by 90% to four trials (precision/recall/NPV/specificity: 35.7%/100.0%/100.0%/95.5%). Conclusion: By leveraging NLP and IE technologies, automated ES could dramatically increase the trial screening efficiency of oncologists and enable participation of small practices, which are often left out from trial enrollment. The algorithm has the potential to significantly reduce the effort to execute clinical research at a point in time when new initiatives of the cancer care community intend to greatly expand both the access to trials and the number of available trials. Electronic supplementary material The online version of this article (doi:10.1186/s12911-015-0149-3) contains supplementary material, which is available to authorized users

Improved chemotherapy modeling with RAG-based immune deficient mice.

We have previously characterized an acute myeloid leukemia (AML) chemotherapy model for SCID-based immune deficient mice (NSG and NSGS), consisting of 5 days of cytarabine (AraC) and 3 days of anthracycline (doxorubicin), to simulate the standard 7+3 chemotherapy regimen many AML patients receive. While this model remains tractable, there are several limitations, presumably due to the constitutional Pkrdcscid (SCID, severe combined immune deficiency) mutation which affects DNA repair in all tissues of the mouse. These include the inability to combine preconditioning with subsequent chemotherapy, the inability to repeat chemotherapy cycles, and the increased sensitivity of the host hematopoietic cells to genotoxic stress. Here we attempt to address these drawbacks through the use of alternative strains with RAG-based immune deficiency (NRG and NRGS). We find that RAG-based mice tolerate a busulfan preconditioning regimen in combination with either AML or 4-drug acute lymphoid leukemia (ALL) chemotherapy, expanding the number of samples that can be studied. RAG-based mice also tolerate multiple cycles of therapy, thereby allowing for more aggressive, realistic modeling. Furthermore, standard AML therapy in RAG mice was 3.8-fold more specific for AML cells, relative to SCID mice, demonstrating an improved therapeutic window for genotoxic agents. We conclude that RAG-based mice should be the new standard for preclinical evaluation of therapeutic strategies involving genotoxic agents