Sa1869 Retinoic Acid Elicits a Coordinated Expression of Gut Homing Markers on T Lymphocytes With Oral Typhoid, but Not Viral, Vaccines in Zambian Men

Abstract We studied the effects of cis-retinoic acid (cisRA) on the clonogenic growth of samples of leukemic cells from 35 patients with acute nonlymphocytic leukemia (ANLL). We observed significant inhibition of leukemic colony growth in 17 samples by 10(-7) to 10(-6)M cisRA. However, we found that retinoid exposure resulted in striking stimulation of clonal growth in ten samples at the same drug concentrations. With the exception of cases with promyelocytic features, there was no morphologic or functional evidence that cisRA induced the leukemic blasts to differentiate. Both inhibition and stimulation were dose-dependent and observable at pharmacologically achievable levels of cisRA. Leukemic cells with monocytic features more frequently demonstrated a stimulatory response than did those without monocytic features. Depletion of T lymphocytes and monocytes did not alter the type of growth response. Assays for cellular retinoic acid- binding protein (CRABP) were performed on five samples (two with inhibitory growth responses, two with stimulatory responses, and one with no growth) and failed to reveal detectable levels of CRABP in any case. The addition of cisRA to liquid suspensions of leukemic cells produced no significant change in the number of viable cells. We conclude that the effects of cisRA on leukemic colony growth are not cytotoxic and not mediated by T lymphocytes, monocytes, or CRABP. More importantly, cisRA appears to enhance the growth of certain human leukemia cells in vitro. Taking into account the increasing use of retinoids in clinical trials for patients with leukemia, the latter findings may represent a significant cautionary note.

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Retinoic Acid Promotes Proliferation and Induces Expression of Retinoic Acid Receptor-α Gene in Murine T Lymphocytes

Cellular Immunology ◽

10.1006/cimm.1993.1284 ◽

1993 ◽

Vol 152 (1) ◽

pp. 240-248 ◽

Cited By ~ 20

Author(s):

Aharon Friedman ◽

Orna Halevy ◽

Michal Schrift ◽

Yossef Arazi ◽

David Sklan

Keyword(s):

Retinoic Acid ◽

T Lymphocytes ◽

Retinoic Acid Receptor ◽

Acid Receptor ◽

Retinoic Acid Receptor Α

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Polyclonal hematopoietic reconstitution in leukemia patients at remission after suppression of specific gene rearrangements [see comments]

Blood ◽

10.1182/blood.v82.2.606.606 ◽

1993 ◽

Vol 82 (2) ◽

pp. 606-612 ◽

Cited By ~ 11

Author(s):

F Lo Coco ◽

PG Pelicci ◽

F D'Adamo ◽

D Diverio ◽

G Alimena ◽

...

Keyword(s):

Retinoic Acid ◽

T Lymphocytes ◽

Southern Blot ◽

X Chromosome ◽

Promyelocytic Leukemia ◽

Gene Rearrangements ◽

Aberrant Methylation ◽

Allogeneic Bone ◽

Hematopoietic Reconstitution ◽

Methylation Patterns

Abstract Clonality studies of hematopoietic reconstitution after remission were performed in 24 female patients (pts) with leukemias characterized by specific molecular markers. At diagnosis, 13 pts had promyelocytic leukemia (PML) retinoic acid receptor-alpha (RAR-alpha)-rearranged acute promyelocytic leukemia (APL), 8 Philadelphia positive (Ph′+) break-point cluster region (BCR+) chronic myeloid leukemia (CML), and 3 Ph′+ (BCR+) acute lymphoblastic leukemia (ALL). All pts were analyzed at presentation and after Southern blot suppression of specific rearrangements after various treatments, including conventional chemotherapy, autologous or allogeneic bone marrow transplant (BMT), all-trans retinoic acid, and alpha-2b interferon. DNA from BM samples collected at diagnosis and, during remission phases, were subjected to Southern blot analysis with the M27 beta probe to detect X chromosome methylation differences, and with BCR, in CML and ALL cases, or PML/RAR- a probes for gene rearrangements, in APL cases. Twenty-one of the 24 pts had polyclonal methylation patterns at remission, together with disappearance of the specific rearrangement, whereas 3 pts retained the same single unmethylated DXS255 allele detected at diagnosis despite no evidence of gene rearrangement. Concerning these 3 pts, such an apparently clonal pattern was also observed in one case in T lymphocytes and skin-derived DNA; in a second case in BM fibroblasts and T lymphocytes; and, in the third case, in blood mononuclear cells obtained from her healthy female BM donor. All these 3 pts are in unmaintained clinical and cytogenetic remission after more than 20 months off therapy. These data suggest that (1) polyclonal and presumably normal hematopoiesis occurs in APL, CML, and Ph′+ ALL pts once the major burden of leukemic cells carrying a specific rearrangement is suppressed by treatment; and (2) unbalanced X chromosome methylation patterns, or aberrant methylation of X chromosome regions may be observed in some cases, most likely reflecting constitutional features simulating a clonal picture.

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Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.14.7.4872-4877.1994 ◽

1994 ◽

Vol 14 (7) ◽

pp. 4872-4877

Author(s):

A Carè ◽

U Testa ◽

A Bassani ◽

E Tritarelli ◽

E Montesoro ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Retinoic Acid ◽

T Cell ◽

T Lymphocytes ◽

T Cell Activation ◽

Cell Activation ◽

Rnase Protection ◽

Activated T Lymphocytes

We investigated the expression of HOXB cluster genes in purified phytohemagglutinin (PHA)-activated T lymphocytes from normal adult peripheral blood by reverse transcription PCR and RNase protection. These genes are not expressed in quiescent T cells, except for barely detectable B1 RNA. After the PHA stimulus, HOXB gene activation initiates coordinately as a rapid induction wave in the 3'-->5' cluster direction (i.e., from HOXB1 through B9 genes). Thus, (i) expression of the foremost 3'-located B1 and B2 genes peaks 10 min after PHA addition and then rapidly declines, (ii) activation of B3, B4, and B5 begins 10 min after PHA addition and peaks at later times (i.e., at 120 min for B5), (iii) B6, B7, and B9 are expressed at a low level starting at later times (45 to 60 min), and (iv) B8 remains silent. Treatment of PHA-activated T lymphocytes with antisense oligonucleotides to B2 or B4 mRNA causes a drastic inhibition of T-cell proliferation and a decreased expression of T-cell activation markers (i.e., interleukin 2 and transferrin receptors). Similarly, treatment of CEM-CCRF, Peer, and SEZ627 T acute lymphocytic leukemia cell lines with anti-B4 oligomer markedly inhibits cell proliferation. Finally, T cells stimulated by a low dosage of PHA in the presence of 1 microM retinoic acid show a marked increase of both HOXB expression, particularly B2, and cell proliferation. These studies provide novel evidence on the role of HOX genes in adult cell proliferation. (i) Coordinate, early activation of HOXB genes from the 3'-->5' cluster side apparently underlies T-cell activation. (ii) The expression pattern in adult PHA-activated T cells is strikingly similar to that observed in retinoic acid-induced teratocarcinoma cells (A. Simeone, D. Acampora, L. Arcioni, P. W. Andres, E. Boncinelli, and F. Mavilio, Nature (London) 346:763-766, 1990), thus suggesting that molecular mechanisms underlying HOX gene expression in the earliest stages of development may also operate in activated adult T lymphocytes.

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