Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The outcome for adult patients with BCR-ABL-positive acute lymphoblastic leukemia (ALL) remains dismal and long-term survival can hardly be achieved except by allogeneic hematopoietic stem cell transplantation (HSCT). The Japan Adult Leukemia Study Group (JALSG) has recently started a phase 2 trial with intensive chemotherapy and imatinib for newly diagnosed BCR-AB-positive ALL patients, and we present here the interim results for the first 24 patients. All patients except one case of early death (96%) attained complete remission (CR) after a single course of remission induction therapy. Polymerase chain reaction (PCR) negativity was achieved in 28% of the patients on day 28, in 50% on day 63, and in up to 78% during the follow-up period. The toxicity profile was almost similar to that with chemotherapy alone. As a result, 15 patients (63%) could receive an allogeneic HSC transplant during their first CR. Although the number of patients is small and the observation period is too short, the combination therapy is very promising and produces high-quality CR for most newly diagnosed patients with BCR-ABL-positive ALL. This is especially useful because it provides the patients with a better chance to receive an allogeneic HSC transplant.
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PMID:Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. 1531 63

Hox genes are clearly implicated in leukemia; however, neither the specificity of the leukemogenic potential among Hox genes of different paralog groups nor the role of the homeodomain is clear. We tested the leukemogenic potential of various NUP98-Hox fusion genes alone and with MEIS1. All genes tested had a significant overlapping effect in bone marrow cells in vitro. However, not all formed strong leukemogenic NUP98 fusion genes; but together with overexpression of MEIS1, all induced myeloid leukemia. This phenomenon was also seen with NUP98 fusions containing only the homeodomain of the corresponding Hox protein. We then exploited the strong transforming potential of NUP98-HOXD13 and NUP98-HOXA10 to establish preleukemic myeloid lines composed of early myeloid progenitors with extensive in vitro self-renewal capacity, short-term myeloid repopulating activity, and low propensity for spontaneous leukemic conversion. We also showed that MEIS1 can efficiently induce their conversion to leukemic stem cells, thus providing a novel model for the study of leukemic progression. In contrast to the leukemogenic effect of most of the Hox genes tested, HOXB4 has the ability to increase the self-renewal of hematopoietic stem cells without disrupting normal differentiation. On the basis of the discovery that the leukemogenic gene HOXA9 can also expand hematopoietic stem cells, we compared the ability of NUP98-Hox fusions to that of HOXB4 to trigger HSC expansion in vitro. Our preliminary results indicate that the expanding potential of HOXB4 is retained and even augmented by fusion to NUP98. Moreover, even greater expansion may be possible using Abd-B-like Hox fusions genes.
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PMID:Hox genes: from leukemia to hematopoietic stem cell expansion. 1595 3

Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
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PMID:Cell intrinsic alterations underlie hematopoietic stem cell aging. 1596 97

Reports of neoplasia related to insertional activation of protooncogenes by retroviral vectors have raised serious safety concerns in the field of gene therapy. Modification of current approaches is urgently required to minimize the deleterious consequences of insertional mutagenesis. In this issue of the JCI, Adjali and colleagues report on their treatment of SCID mice lacking the 70-kDa protein tyrosine kinase, ZAP-70, with direct intrathymic injection of a ZAP-70-expressing T cell-specific lentiviral vector, which resulted in T cell reconstitution. Using lentiviral vectors and in situ gene transfer may represent a safer approach than using retroviral vectors for ex vivo gene transfer into HSCs, avoiding 3 factors potentially linked to leukemogenesis, namely HSC targets, ex vivo transduction and expansion, and standard Moloney leukemia virus-based retroviral vectors.
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PMID:A new direction for gene therapy: intrathymic T cell-specific lentiviral gene transfer. 1607 64

In this study we have examined the interaction of CD44 (a major hyaluronan (HA) receptor) with a RhoA-specific guanine nucleotide exchange factor (leukemia-associated RhoGEF (LARG)) in human head and neck squamous carcinoma cells (HNSCC-HSC-3 cell line). Immunoprecipitation and immunoblot analyses indicate that CD44 and the LARG protein are expressed in HSC-3 cells and that these two proteins are physically associated as a complex. HA-CD44 binding induces LARG-specific RhoA signaling and phospholipase C epsilon (PLC epsilon) activity. In particular, the activation of RhoA-PLC epsilon by HA stimulates inositol 1,4,5-triphosphate production, intracellular Ca2+ mobilization, and the up-regulation of Ca2+/calmodulin-dependent kinase II (CaMKII), leading to phosphorylation of the cytoskeletal protein, filamin. The phosphorylation of filamin reduces its interaction with filamentous actin, promoting tumor cell migration. The CD44-LARG complex also interacts with the EGF receptor (EGFR). Most importantly, the binding of HA to the CD44-LARG-EGFR complex activates the EGFR receptor kinase, which in turn promotes Ras-mediated stimulation of a downstream kinase cascade including the Raf-1 and ERK pathways leading to HNSCC cell growth. Using a recombinant fragment of LARG (the LARG-PDZ domain) and a binding assay, we have determined that the LARG-PDZ domain serves as a direct linker between CD44 and EGFR. Transfection of the HSC-3 cells with LARG-PDZcDNA significantly reduces LARG association with CD44 and EGFR. Overexpression of the LARG-PDZ domain also functions as a dominant-negative mutant (similar to the PLC/Ca2+-calmodulin-dependent kinase II (CaMKII) and EGFR/MAPK inhibitor effects) to block HA/CD44-mediated signaling events (e.g. EGFR kinase activation, Ras/RhoA co-activation, Raf-ERK signaling, PLC epsilon-mediated inositol 1,4,5-triphosphate production, intracellular Ca2+ mobilization, CaMKII activity, filamin phosphorylation, and filamin-actin binding) and to abrogate tumor cell growth/migration. Taken together, our findings suggest that CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLC epsilon-Ca2+ signaling, and Raf/ERK up-regulation required for CaMKII-mediated cytoskeleton function and in head and neck squamous cell carcinoma progression.
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PMID:Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. 1656 89

In our screening program for new photosensitizers from the Malaysian biodiversity, we found five pheophorbide-related compounds from the leaves and stems of Aglaonema simplex. Detailed spectroscopic analyses showed that compounds 1-3 and 5 are pheophorbide and hydroxy pheophorbide derivatives of chlorophyll a and b. Compound 4, identified as 15(1)-hydroxypurpurin-7-lactone ethyl methyl diester, was isolated for the first time from the Araceae family. An MTT-based short-term survival assay showed that all five compounds exhibit moderate-to-strong photocytotoxic activities towards human leukemia (HL60) and two oral squamous carcinoma cell lines (HSC-2 and HSC-3). Compounds 4 and 5 showed the strongest photocytotoxicities, with IC(50) values of 0.30-0.41 muM (Table 2). Compounds 1-3 with Et chains at C(17(3)) were less photocytotoxic than the parent pheophorbide a (5).
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PMID:Photocytotoxic pheophorbide-related compounds from Aglaonema simplex. 1719 61

Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell-cell and cell-matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK(flox/flox) hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.
Leukemia 2007 Aug
PMID:Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells. 1756 20

The correlation between the cytotoxicity of seven vitamin K2 (menaquinone) derivatives and thirteen chemical descriptors determined by CONFLEX5/CAChe Worksystem 4.9 (PM3) was investigated. After determination of the conformation of the seven vitamin K2 derivatives and approximation to the molecular form present in vivo (biomimetic) by CONFLEX5, the most stable structure was then determined by CAChe Worksystem 4.9 MOPAC (PM3). The vitamin K2 derivatives with one to three isoprenyl units [1-3] showed an extended form, whereas those with four to seven isoprenyl units [4-7] displayed a spherical form. The human hepatocellular carcinoma HepG2 cells displayed a good correlation between cytotoxicity and all the descriptors except for the electron affinity and lowest unoccupied molecular orbital energy (E(LUMO)). The absolute hardness (eta)--absolute electron negativity (chi) activity diagram determined by this calculation method may be useful for estimating the cytotoxic activity of vitamin K2 derivatives against HepG2 cells. The human squamous cell carcinoma HSC-2 and HSC-3 cells showed similar correlation. The human promyleocytic leukemia HL-60 cells showed the good correlation between cytotoxicity and molecular length. The present study demonstrates for the first time the best correlation between cytotoxic activity and molecular shape or molecular weight of vitamin K2 derivatives, regardless of the type of target cells.
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PMID:QSAR of molecular structure and cytotoxic activity of vitamin K2 derivatives with concept of absolute hardness. 1822 71

Retroviral vector-mediated HSC gene therapy has been used to treat individuals with a number of life-threatening diseases. However, some patients with SCID-X1 developed retroviral vector-mediated leukemia after treatment. The selective growth advantage of gene-modified cells in patients with SCID-X1 suggests that the transgene may have played a role in leukemogenesis. Here we report that 2 of 2 dogs and 1 of 2 macaques developed myeloid leukemia approximately 2 years after being transplanted with cells that overexpressed homeobox B4 (HOXB4) and cells transduced with a control gammaretroviral vector that did not express HOXB4. The leukemic cells had dysregulated expression of oncogenes, a block in myeloid differentiation, and overexpression of HOXB4. HOXB4 knockdown restored differentiation in leukemic cells, suggesting involvement of HOXB4. In contrast, leukemia did not arise from the cells carrying the control gammaretroviral vector. In addition, leukemia did not arise in 5 animals with high-level marking and polyclonal long-term repopulation following transplantation with cells transduced with an identical gammaretrovirus vector backbone expressing methylguanine methyltransferase. These findings, combined with the absence of leukemia in many other large animals transplanted with cells transduced with gammaretroviral vectors expressing genes other than HOXB4, show that HOXB4 overexpression poses a significant risk of leukemogenesis. Our data thus suggest the continued need for caution in genetic manipulation of repopulating cells, particularly when the transgene might impart an intrinsic growth advantage.
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PMID:High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. 1835 48

Bone marrow engraftment in the context of hematopoietic stem cell and progenitor (HSC/P) transplantation is based on the ability of intravenously administered cells to lodge in the medullary cavity and be retained in the appropriate marrow space, a process referred to as homing. It is likely that homing is a multistep process, encompassing a sequence of highly regulated events that mimic the migration of leukocytes to inflammatory sites. In leukocyte biology, this process includes an initial phase of tethering and rolling of cells to the endothelium via E- and P-selectins, firm adhesion to the vessel wall via integrins that appear to be activated in an "inside-out" fashion, transendothelial migration, and chemotaxis through the extracellular matrix (ECM) to the inflammatory nidus. For HSC/P, the cells appear to migrate to the endosteal space of the bone marrow. A second phase of engraftment involves the subsequent interaction of specific HSC/P surface receptors, such as alpha(4)beta(1) integrin receptors with vascular cell-cell adhesion molecule-1 and fibronectin in the ECM, and interactions with growth factors that are soluble, membrane, or matrix bound. We have utilized knockout and conditional knockout mouse lines generated by gene targeting to study the role of Rac1 and Rac2 in blood cell development and function. We have determined that Rac is activated via stimulation of CXCR4 by SDF-1, by adhesion via beta(1) integrins, and via stimulation of c-kit by the stem cell factor-all of which involved in stem cell engraftment. Thus Rac proteins are key molecular switches of HSC/P engraftment and marrow retention. We have defined Rac proteins as key regulators of HSC/P cell function and delineated key unique and overlapping functions of these two highly related GTPases in a variety of primary hematopoietic cell lineages in vitro and in vivo. Further, we have begun to define the mechanisms by which each GTPase leads to specific functions in these cells. These studies have led to important new understanding of stem cell bone marrow retention and trafficking in the peripheral circulation and to the development of a novel small molecule inhibitor that can modulate stem cell functions, including adhesion, mobilization, and proliferation. This chapter describes the biochemical footprint of stem cell engraftment and marrow retention related to Rho GTPases. In addition, it reviews abnormalities of Rho GTPases implicated in human immunohematopoietic diseases and in leukemia/lymphoma.
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PMID:Rho GTPases and regulation of hematopoietic stem cell localization. 1837 78


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