Despite its dual role in determining cell fate in a wide array of solid cancer cell lines, autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis. However, autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein, though the molecular mechanism remains elusive. Nevertheless, since it can induce cooperation with apoptosis and differentiation in response to autophagic signals, autophagy can be manipulated for a better therapy on acute myeloid leukemia.
Antineoplastic Agents ; therapeutic use ; Apoptosis ; Apoptosis Regulatory Proteins ; metabolism ; Autophagy ; drug effects ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; metabolism ; pathology ; Leukemia, Promyelocytic, Acute ; drug therapy ; metabolism ; pathology ; Molecular Targeted Therapy ; Oncogene Proteins, Fusion ; metabolism ; Tretinoin ; therapeutic use

In general, a 2-yr disease-free duration is recommended before kidney transplantation (KT) in end-stage renal disease (ESRD) patients who also have acute leukemia. However, the optimal disease-free interval has not been specified for all subtypes of acute leukemia. Among these subtypes, acute promyelocytic leukemia (APL) shows a favorable prognosis and low relapse rate compared to other types of leukemia. We here report KT after complete remission (CR) of APL in an ESRD patient. Irreversible kidney injury developed in a 23-yr-old man with APL. First, we induced CR and subsequently performed KT 7 months after the achievement of CR. The patient's clinical course after KT was favorable, without allograft rejection or relapse of APL up to1 yr after KT. On the basis of our clinical experience, it is suggested that a long wait may not be necessary before KT in patients with ESRD and APL.
Adult ; Antineoplastic Agents/therapeutic use ; Arsenicals/therapeutic use ; Bone Marrow Cells/pathology ; Humans ; Kidney Failure, Chronic/*therapy/ultrasonography ; *Kidney Transplantation ; Leukemia, Promyelocytic, Acute/*diagnosis/drug therapy ; Male ; Oxides/therapeutic use ; Receptors, Retinoic Acid/genetics/metabolism ; Remission Induction

Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare, and the presence of CNS symptoms at the time of diagnosis of APL is even rarer. We report 2 cases of APL presenting with CNS involvement. A 43-yr-old woman presented with easy bruising and stuporous mentality. Her complete blood count (CBC) revealed leukocytosis with increased blasts. Bone marrow (BM) analysis was carried out, and the diagnosis of APL was confirmed. This was done by cytogenetic analysis and demonstration of PML-RARalpha rearrangement by reverse transcriptase PCR in the BM cells. A lumbar puncture was performed to investigate the cause of her stuporous mentality, and her cerebrospinal fluid (CSF) analysis revealed 97% leukemic promyelocytes. Despite systemic and CNS therapy, she died due to septic shock by infection and rapid disease progression only 3 days after her admission. Another patient, a 3-yr-old girl, presented with easy bruising and epistaxis, and her CBC showed pancytopenia with increased blasts. BM studies confirmed APL. Quantitative PCR for PML-RARalpha in the BM cells revealed a PML-RARalpha/ABL ratio of 0.33 and CSF analysis revealed 9.5% leukemic promyelocytes (2 of 21 cells). She received induction chemotherapy and intrathecal therapy and achieved complete remission (CR) in the BM and CNS. She has been maintained in the CR status for the past 31 months. Thus, patients with APL must be evaluated for CNS involvement if any neurological symptoms are present at the time of diagnosis.
Adult ; Antineoplastic Agents/therapeutic use ; Bone Marrow Cells/metabolism/pathology ; Central Nervous System/pathology ; Child, Preschool ; Contusions/etiology ; Epistaxis/etiology ; Female ; Granulocyte Precursor Cells/pathology ; Humans ; Karyotyping ; Leukemia, Promyelocytic, Acute/*cerebrospinal fluid/drug therapy/pathology ; Oncogene Proteins, Fusion/analysis/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Spinal Puncture ; Tomography, X-Ray Computed ; Tretinoin/therapeutic use

OBJECTIVETo investigate the effects of CDA-II alone or combined with cAMP on the retinoic acid (RA)-resistant acute promyelocytic leukemia (APL) cells.

METHODSThe RA-resistant cell line NB4-R2 was used as an in vitro model and treated with CDA-II alone or in combination with cAMP. Cell apoptosis was assessed by morphology observation, distribution of cellular DNA contents and sub-G1 cell population. The level of Bcl-2 was detected by flow cytometry, DNA "ladder" was detected by agarose-electrophoresis.

RESULTSCDA-II could induce NB4-R2 cell apoptosis through decreasing the level of cellular anti-apoptotic protein Bcl-2. cAMP could significantly enhance the role of CDA-II. Bcl-2 positive cell rates decreased to (15.1 +/- 4.8)% and (7.3 +/- 2.9)% in NB4-R2 cells treated with 1 mg/ml CDA-II plus 100 micromol/L cAMP for 48 h and 72 h, respectively. While 100 micromol/L of cAMP could decrease Bcl-2 positive NB4-R2 cells from (92.0 +/- 0.6)% to (75.3 +/- 2.0)%.

CONCLUSIONSCDA-II combined with cAMP could exert potent apoptotic effect on RA-resistant APL cells.

Animals ; Apoptosis ; drug effects ; CD11c Antigen ; metabolism ; Cells, Cultured ; Cyclic AMP ; pharmacology ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; pathology ; Peptides ; pharmacology ; Phenylacetates ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Tretinoin ; pharmacology

OBJECTIVETo study the role of inhibitor of differentiation 1 (ID1) in ATRA-induced acute promyelocytic leukemia (APL) cells differentiation.

METHODSThe expression of ID1 was detected by cDNA microarray, cycloheximide inhibition test, real-time RT-PCR and western blot.

RESULTSThe expression of ID1 gene was up-regulated in ATRA-induced NB4 cells and APL cells from two patients and was independent on other proteins synthesis. ID1 expression level reached the peak at 2 h in NB4 cells induced by ATRA, its relative expression level was (359.4 +/- 48.7)-fold greater than control. ID1 expression level reached the peak at 2 h in bone marrow cells from APL patents treated with ATRA, and its level detected 3 times in one of the patient was (311.1 +/- 48.7) fold of control. The expression of ID1 protein was not up-regulated in ATRA resistant NB4-R2 cells after ATRA treatment.

CONCLUSIONID1 may be involved in ATRA-induced granulocytic differentiation as an ATRA-targeted gene.

Antineoplastic Agents ; therapeutic use ; Cell Differentiation ; Humans ; Inhibitor of Differentiation Protein 1 ; genetics ; metabolism ; Leukemia, Promyelocytic, Acute ; drug therapy ; metabolism ; pathology ; Oligonucleotide Array Sequence Analysis ; Tretinoin ; therapeutic use

BACKGROUNDCurrently, resistance and relapse are still major problems in acute promyelocytic leukemia (APL) cases. Thus, new agents that override the resistance are crucial to the development of curative therapies for APL. In this study, we investigated the effects of berbamine on the proliferation of APL cell line NB4 and its possible mechanisms.

METHODSNB4 cells were treated with berbamine at different concentrations (0-64 microg/ml) for 72 hours. MTT assay was used to determine proliferation inhibition of NB4 cells. Cell apoptosis was evaluated by both flow cytometry (FCM) and morphological examination. PML/RAR-alpha and survivin mRNAs were measured by nested-RT-PCR and RT-PCR, respectively. Activated-caspase 3 was determined by FCM.

RESULTSBerbamine greatly inhibited the proliferation of NB4 cells in dose- and time-dependent manners, and its IC50 value was 3.86 microg/ml at 48 hours. Both morphological observations and FCM results showed that berbamine induced apoptosis of NB4 cells with concomitant increase of activated caspase-3 and decrease of survivin mRNA. After treatment with berbamine at 8 microg/ml for 48 hours, the percentage of apoptotic cells increased from 2.83% to 58.44% (P<0.01), and the percentage of cells with activated-caspase 3 elevated from 2.06% to 70.89% (P<0.01), whereas, level of survivin mRNA was reduced to 38.24% of control (P<0.01). However, no significant change was observed in PML/RAR-alpha mRNA.

CONCLUSIONSBerbamine induces caspase-3-dependent apoptosis of leukemia NB4 cells via survivin-mediated pathway, suggesting that berbamine may be a novel potential agent against APL with a mechanism distinct from that of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

Alkaloids ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Benzylisoquinolines ; pharmacology ; Caspase 3 ; physiology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Humans ; Inhibitor of Apoptosis Proteins ; Leukemia, Promyelocytic, Acute ; drug therapy ; pathology ; Microtubule-Associated Proteins ; genetics ; physiology ; Neoplasm Proteins ; genetics ; physiology ; Oncogene Proteins, Fusion ; genetics ; Transcription, Genetic ; drug effects

OBJECTIVETo investigate the chronic hepatic damage in acute promyelocytic leukemia (APL) patients long-term treated with tetra-arsonic tetra-sulfide (As(4)S(4)).

METHODSThe periodical liver biochemical examinations and ultrasonography results and hepatic fibrosis indicators (P III NP and type IV collagen) of patients were analysed.

RESULTS106 APL patients treated with As(4)S(4), the median follow-up time was 36 months (6 - 72). The HCV(-) group includes 84 APL patients. During the first course the abnormal rate of the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was 16.7% and 14.5% (higher than the two times of the normal value), the ALT, AST, gamma-glyoxylate aminotransferase (GGT) levels during the first course were statistically higher than As4S4 treatment before (P < 0.05). There were no statistically differences between the ALT, AST, GGT levels after and before treating with As(4)S(4) in half a year, one year, two year, more than three years (P > 0.05). Other biochemical indicators such as ALP, LDH, TBIL, DBIL, TP, ALB, A/G, BUN, CRE, there were no significantly differences before and after As(4)S(4) treatment (P > 0.05). The HCV(+) group includes 22 APL patients, during the first course, the abnormal rate of the ALT, AST were 63.6% and 59.1%, but at the 2 year, more than 3 years there were no significantly differences compared with As(4)S(4) treatment before (P > 0.05). 42 APL patients were treated with As(4)S(4) more than 3 years, in 33 HCV(-) APL patients, two APL patients had splenomegaly, one APL patient's breadth of the portal vein was wider than 1.4 cm, 21 APL patients had fatty liver (63.6%). The hepatic fibrosis indicators of the 16 APL patients were all normal. In 9 HCV(+) APL patients, 4 APL patients had splenomegaly, 2 APL patients, breadth of portal vein were wider than 1.4 cm, 6 APL patients had fatty liver (66.7%). 6 patients were examined with the hepatic fibrosis indicators, 2 patients, were higher than the normal value.

CONCLUSIONLong term As(4)S(4) treatment for APL patients had no obvious effects on hepatic function, no obvious hepatic fibrosis and portal hypertension signs at more than 3 years, excepting for the rate of fatty liver was high.

Adolescent ; Adult ; Aged ; Arsenicals ; adverse effects ; chemistry ; Collagen Type IV ; metabolism ; Fatty Liver ; chemically induced ; metabolism ; Female ; Fibrosis ; Follow-Up Studies ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; Liver ; drug effects ; pathology ; Male ; Middle Aged ; Sulfides ; adverse effects ; chemistry ; Young Adult

Arsenic trioxide (As2O3, ATO) is a recently developed drug for the effective treatment of acute promyelocytic leukemia (APL). Experimental studies showed that in vitro differentiation-inducing ability on APL cells of this drug is not significant compared with its in vivo activity. We unexpectedly found recently that hypoxia-mimetic agents and moderate real hypoxia triggered acute myeloid leukemic cells to undergo differentiation. Furthermore, intermittent hypoxia significantly prolonged the survival of the transplanted leukemic mice with inhibition of infiltration and induction of differentiation of leukemic cells. In the following works, molecular mechanisms of hypoxia-induced differentiation were investigated and some interesting results have been obtained. This review will shortly summarize the related progresses and discuss the questions remained to be further investigated.
Animals ; Antineoplastic Agents ; therapeutic use ; Arsenicals ; therapeutic use ; Cell Transformation, Neoplastic ; drug effects ; Humans ; Hypoxia ; physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit ; pharmacology ; Leukemia ; drug therapy ; pathology ; Leukemia, Promyelocytic, Acute ; drug therapy ; pathology ; Oxides ; therapeutic use

OBJECTIVETo explore the myelo-protection effect of mdr1 transfected cord blood cells (CBMNCs) graft against high-dose homoharringtonine leukemia-bearing severe combined immunodeficient (SCID) mice model.

METHODSMultidrug resistant (mdr1)gene was transferred into CBMNCs by a retrovirus vector, containing full-length cDNA of human mdr1 gene. CBMNCs and high-titer retrovirus supernatant were cocultured with cytokine combinations for 5 - 6 days. The SCID mouse models bearing human HL-60 cell leukemia were divided into three groups. Group A received tail vein injection of 2 x 10(6) mdr1 gene transduced CBMNCs at day 1 and 3, groups B and C 2 x 10(6) un-transduced CBMNCs and same volume of normal saline, respectively. The 3 groups of the mouse model were treated with weekly escalated doses of homoharringtonine. The peripheral white blood cell (WBC) counts, the human leukemia cells percentage in peripheral blood, the histological findings of main organs were assayed. The CD33 positive HL-60 cells in bone marrow were determined by flow cytometry. The function and expression of mdr1 gene were examined by PCR, immunochemistry (IC) and DNR extrusion test in vivo.

RESULTS(1) mdr1 gene was transferred into CBMNCs successfully and the transfection frequency was 30%. (2) Leukemia SCID mice were xenotransplanted with mdr1-transfected BMMNCs by a programmed procedure and could be used as a valuable model for in vivo evaluating myelo-protection effects. (3) The transfected mice could tolerate homoharringtonine 5 approximately 6 folds higher than conventional dose and kept peripheral WBC count at a mean of 3 x 10(9)/L, with the peripheral human myeloid leukemia cells percentage decreasing to less than 5%. Histological examination showed that there was no leukemia infiltration in the main organs, the CD33 positive HL-60 cells in bone marrow were less than 5%. (4) The repopulation frequency of the transfected CBMNs in marrow were 9.13%. DNR extrusion test confirmed that the P-gp product maintained its biological function in the marrow.

CONCLUSIONmdr1 transferred-human CBMNC can xenotransplanted and repopulated in leukemia-bearing SCID mouse and are protected from chemotherapy-induced myelosuppression.

ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; adverse effects ; therapeutic use ; Cord Blood Stem Cell Transplantation ; methods ; Female ; Fetal Blood ; cytology ; Genetic Vectors ; HL-60 Cells ; Harringtonines ; administration & dosage ; adverse effects ; therapeutic use ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; pathology ; surgery ; Leukocytes, Mononuclear ; cytology ; metabolism ; transplantation ; Male ; Mice ; Mice, SCID ; Random Allocation ; Retroviridae ; genetics ; Transfection ; Treatment Outcome ; Xenograft Model Antitumor Assays

Adult ; Antineoplastic Agents ; adverse effects ; Arsenicals ; adverse effects ; Bone Marrow ; pathology ; Bone Marrow Diseases ; chemically induced ; Child ; Female ; Humans ; Infusions, Intravenous ; Leukemia, Promyelocytic, Acute ; drug therapy ; Male ; Necrosis ; Oxides ; adverse effects