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1.  Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia 
Leukemia research  2012;37(1):28-31.
Purpose
The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy.
Methods
Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone.
Results
Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient’s (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD.
Conclusions
A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.
doi:10.1016/j.leukres.2012.09.016
PMCID: PMC3753071  PMID: 23046833
AML; D14 BM biopsy; Re-induction
2.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
doi:10.1038/ng.2468
PMCID: PMC3674561  PMID: 23143597
3.  Feasibility of low dose interleukin-2 therapy following T cell-depleted non-myeloablative allogeneic hematopoietic stem cell transplantation from HLA matched or mismatched family member donors 
Cancer investigation  2011;29(1):56-61.
High relapse rates and infections remain primary causes of failure in non-myeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T cell-depleted nonmyeloablative hematopoietic stem cell transplant.
Methods
Patients received T cell depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment, < grade 2 acute GVHD at time of study entry, and no severe end organ damage were eligible and received IL2 starting 6 weeks after the first day of stem cell infusion. Patients received 1 mu/m2 daily for 5 days each week for 4 weeks followed by a 2 week rest period for a 6 week cycle to continue for up to 1 year.
Results
Eight patients aged 28–69 were treated. Significant toxicities were limited to GVHD of the skin ≤ grade 2 in 3 patients and severe fatigue in 4 patients, limiting the duration of therapy. Two of the 8 patients died of relapsed disease and one from CMV. With a median overall duration of follow up of survivors of 48 months, five patients (63%) remain alive and in continuous complete remission.
doi:10.3109/07357907.2010.535055
PMCID: PMC3619422  PMID: 21166499
Non-myeloablative Allogeneic Transplantation; Leukemia /Lymphoma; IL-2; NK cells
4.  Utilization of Pathway Signatures to Reveal Distinct Types of B Lymphoma in the Eμ-myc Model and Human Diffuse Large B-Cell Lymphoma 
Cancer research  2008;68(20):8525-8534.
The Eμ-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Eμ-myc mice associated with time of tumor onset. Furthermore, one form of Eμ-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma.
doi:10.1158/0008-5472.CAN-08-1329
PMCID: PMC3617051  PMID: 18922927
5.  Clinically undiagnosed enteropathy associated T-cell lymphoma type II presenting with prolonged lower gastrointestinal tract symptoms: report of an autopsy case and review of diagnostic challenges and clinicopathological correlation 
An elderly patient with watery diarrhea for 3 months received extensive laboratory, radiographic and upper and lower gastrointestinal (GI) endoscopic work up including colonic biopsies, but a diagnosis was not established before death. At autopsy enteropathy associated T-cell lymphoma-type II (EATL-II) with multifocal mucosal involvement of the jejunum was identified. The colon was completely uninvolved grossly and microscopically. The stomach showed only subtle lesions grossly but microscopic examination revealed involvement by lymphoma in the stomach as well as other organs in abdomen and chest. The relationship between celiac disease and enteropathy associated T-cell lymphoma, the practical difficulties in establishing the diagnosis and the pathology of T-cell lymphomas affecting the gastrointestinal tract are discussed.
doi:10.3978/j.issn.2078-6891.2012.052
PMCID: PMC3562631  PMID: 23450273
EATL; T-cell lymphoma; enteropathy; celiac disease
7.  SMAD4 is required for development of maximal endotoxin tolerance 
Initial exposure of monocytes/macrophages to lipopolysaccharide (LPS) induces hypo-responsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Molecular mechanisms responsible for endotoxin tolerance are not well defined. We and others have shown that IRAK-M and SHIP-1 proteins, negative regulators of TLR4 signaling, increase in tolerized cells. TGFβ1, an anti-inflammatory cytokine, is up-regulated following LPS stimulation, mediating its effect through SMAD family proteins. Using a monocytic cell line, THP1 we show that LPS activates endogenous SMAD4, inducing its migration into the nucleus and increasing its expression. Secondary challenge with high dose LPS following initial low dose LPS exposure does not increase IRAK-M or SHIP1 protein expression in shSMAD4 THP-1 cells compared with control shLUC THP1 cells. TNF-α concentrations in culture supernatants after second LPS challenge are higher in shSMAD4 THP-1 cells than shLUC THP1 cells, indicating failure to induce maximal tolerance in absence of SMAD4 signaling. Identical results are seen in primary murine macrophages and murine embryonic fibroblasts, demonstrating the biological significance of our findings. TGF-β1 treatment does not increase IRAK-M or SHIP1 protein expression in shSMAD4 THP-1 cells while it does so in shLUC THP1 cells, indicating that TGF-β1 regulates IRAK-M and SHIP1 expression through a SMAD4-dependent pathway. Knockdown of endogenous SHIP1 by shSHIP1 RNA decreases native and inducible IRAK-M protein expression and prevents development of endotoxin tolerance in THP1 cells. We conclude that in THP-1 cells and primary murine cells, SMAD4 signaling is required for maximal induction of endotoxin tolerance via modulation of SHIP1 and IRAK-M.
doi:10.4049/jimmunol.0901601
PMCID: PMC2910367  PMID: 20404275
SMAD4; SHIP1; IRAK-M; LPS; TNF-α; THP1; endotoxin tolerance
8.  Regulation of myeloid leukemia by the cell fate determinant Musashi 
Nature  2010;466(7307):765-768.
Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi-Numb signaling axis4,5. Specifically, we find that chronic phase is marked by high and blast crisis phase by low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced phase disease in vivo. As a possible explanation for the decreased levels of Numb in blast crisis, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML6,7, can trigger expression of the RNA binding protein Musashi2 (Msi2) which in turn represses Numb. Importantly, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for therapy of aggressive leukemias.
doi:10.1038/nature09171
PMCID: PMC2918284  PMID: 20639863
9.  A Role for E2F Activities in Determining the Fate of Myc-Induced Lymphomagenesis 
PLoS Genetics  2009;5(9):e1000640.
The phenotypic heterogeneity that characterizes human cancers reflects the enormous genetic complexity of the oncogenic process. This complexity can also be seen in mouse models where it is frequently observed that in addition to the initiating genetic alteration, the resulting tumor harbors additional, somatically acquired mutations that affect the tumor phenotype. To investigate the role of genetic interactions in the development of tumors, we have made use of the Eμ-myc model of pre-B and B cell lymphoma. Since various studies point to a functional interaction between Myc and the Rb/E2F pathway, we have investigated the role of E2F activities in the process of Myc-induced lymphomagenesis. Whereas the absence of E2F1 and E2F3 function has no impact on Myc-mediated tumor development, the absence of E2F2 substantially accelerates the time of tumor onset. Conversely, tumor development is delayed by the absence of E2F4. The enhanced early onset of tumors seen in the absence of E2F2 coincides with an expansion of immature B lineage cells that are likely to be the target for Myc oncogenesis. In contrast, the absence of E2F4 mutes the response of the lineage to Myc and there is no expansion of immature B lineage cells. We also find that distinct types of tumors emerge from the Eμ-myc mice, distinguished by different patterns of gene expression, and that the relative proportions of these tumor types are affected by the absence of either E2F2 or E2F4. From these results, we conclude that there are several populations of tumors that arise from the Eμ-myc model, reflecting distinct populations of cells that are susceptible to Myc-mediated oncogenesis and that the proportion of these cell populations is affected by the presence or absence of E2F activities.
Author Summary
The diversity of human cancers reflects the variety of genetic changes that cause tumors to emerge and progress. Even for mice engineered with a specific cancer-causing mutation, the resulting tumors are often divergent, reflecting different additional mutations. We wanted to investigate how activities that work together can collaborate in tumorigenesis. Specifically, we are interested in Myc and the E2F family of proteins, intersecting activities that influence a cell's decision to replicate, rest, or die. We made use of an engineered mouse that develops pre-B and B cell lymphoma initiated by Myc and tested whether the loss of particular E2F family members influences these lymphomas. We found that tumor emergence was accelerated by E2F2 loss and delayed by E2F4 loss. We attributed these results to the finding that the mice lacking E2F2 have a greater proportion than usual of the most susceptible, early-stage B lineage cells and the mice lacking E2F4 have fewer of these cells. Distinct tumor types emerged with their relative proportions influenced by E2F2 and E2F4 status. We conclude that the variety of tumors probably reflect different stages of B lymphoid development that respond to Myc and that E2F proteins can influence the proportions of these different stages.
doi:10.1371/journal.pgen.1000640
PMCID: PMC2729385  PMID: 19749980
10.  Loss of β-Catenin Impairs the Renewal of Normal and CML Stem Cells In Vivo 
Cancer cell  2007;12(6):528-541.
SUMMARY
A key characteristic of stem cells and cancer cells is their ability to self-renew. To test if Wnt signaling can regulate the self-renewal of both stem cells and cancer cells in the hematopoietic system, we developed mice that lack β-catenin in their hematopoietic cells. Here we show that β-catenin-deficient mice can form HSCs, but that these cells are deficient in long-term growth and maintenance. Moreover, β-catenin deletion causes a profound reduction in the ability of mice to develop BCR-ABL-induced chronic myelogenous leukemia (CML), while allowing progression of acute lymphocytic leukemia (ALL). These studies demonstrate that Wnt signaling is required for the self-renewal of normal and neoplastic stem cells in the hematopoietic system.
doi:10.1016/j.ccr.2007.11.003
PMCID: PMC2262869  PMID: 18068630

Results 1-10 (10)