Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) and is distinguished from other subsets of AML by its distinctive morphology, specific chromosomal abnormality, associated consumptive coagulopathy, and response to treatment. Interestingly, patients with APL frequently enter complete remission without undergoing a characteristic period of bone marrow hypoplasia. In two cases in this report, complete remission was achieved without bone marrow hypoplasia without further additional course of chemotherapy despite the appearance of persistent malignant cells in the bone marrow after first induction chemotherapy. During the period of treatment, severe coagulopathy occurred in both cases but resolved as the patients entered into remission. Remission in patients with APL may occur even when induction therapy fails to cause marrow hypoplasia or to eradicate replicative cells. To avoid unnecessary exposure to toxic therapy, caution should be exercised in assessing the adequacy of remission induction treatment.
Adult ; Bone Marrow/*pathology ; Cell Differentiation/drug effects ; Granulocytes/*pathology ; Humans ; Leukemia, Promyelocytic, Acute/*drug therapy/pathology ; Male ; Remission Induction/methods

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

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 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

All-trans retinoic acid (ATRA) is the standard induction treatment for acute promyelocytic leukemia (APL). Quite many ATRA-related side effects, including retinoic acid syndrome, were reported. So far, it has rarely been reported that Sweet's syndrome, characterized by fever, neutrophilia, painful erythematous cutaneous plaques, dense dermal infiltrates of mature neutrophils and rapid response to steroid therapy, is associated with ATRA. In the case that Sweet's syndrome associated with ATRA is found, physicians will have to face a great challenge over the possibility of infectious conditions. We present here a case of Sweet's syndrome associated with ATRA. A 35-year-old female with APL developed fever, painful erythematous cutaneous plaques on both cheeks, right wrist and both shins during induction chemotherapy with ATRA. A skin biopsy revealed a dense dermal infiltrate, consisting of mature neutrophils without vasculitis or cutaneous immunoglobulin deposits, which is compatible with Sweet's syndrome. Oral prednisone was administered and the lesions started to improve within 48 hours
Adult ; Biopsy, Needle ; Case Report ; Female ; Follow-Up Studies ; Human ; Leukemia, Promyelocytic, Acute/diagnosis/*drug therapy ; Prednisone/administration & dosage ; Risk Assessment ; Sweet's Syndrome/*chemically induced/drug therapy/*pathology ; Tretinoin/*adverse effects/therapeutic use

OBJECTIVETo study the morphologic and cytogenetic change in acute promyelocytic leukemia (APL) patients during the tetra-arsenic tetra-sulfide (TATS) treatment and the mechanism of TATS.

METHODSThe bone marrow cells of 13 newly diagnosed and 7 recurrent APL patients were studied through FISH and morphology during the TATS treatment by special and repeated marrow culture.

RESULTSCytomorphological study of 8 cases (6 untreated and 2 recurrent) showed that TATS could differentiate APL cells forward to mature granulocytes. There was obvious correlation between the reduced t (15; 17) positive cells and the reduced APL cells (r range 0.7298 - 0.9989). Except one patient with t (11; 17), 19 (13 untreated and 7 recurrent) with translocation t (15; 17) achieved clinical CR including 16 who achieved cytogenetic CR.

CONCLUSIONTATS has a differentiation-inducing effect on untreated and recurrent APL, with haematological CR and cytogenetic CR achieved. Measurement of t (15; 17) positive cells by FISH technique can reflect the change of APL cells objectively.

Adult ; Arsenicals ; therapeutic use ; Bone Marrow ; pathology ; Chromosomes, Human, Pair 15 ; Chromosomes, Human, Pair 17 ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Promyelocytic, Acute ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Recurrence ; Sulfides ; therapeutic use ; Translocation, Genetic

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

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

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

OBJECTIVETo investigate the effects of red orpiment on cell morphology, expression of promyelocytic leukemia (PML) mRNA and its protein localization in NB4 and HL-60 cell lines.

METHODSCell morphology was assayed by Wright's staining and fluorescence staining, while PML mRNA expression was determined by RT-PCR. PML protein localization by evaluated by immunofluorescence staining.

RESULTSThe typical apoptosis was found in NB4 and HL-60 cells after treatment with red orpiment. The fusion protein was no longer observed in NB4 cells, PML protein was relocated, and then degraded. In HL-60 cells, PML protein underwent a similar progress. The expression of promyelocytic leukemia (PML) mRNA was not changed in the treated cells.

CONCLUSIONRed orpiment inhibits the proliferation of leukemia cells by inducing them to undergo apoptosis.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Arsenicals ; pharmacology ; HL-60 Cells ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; metabolism ; pathology ; Medicine, Chinese Traditional ; Neoplasm Proteins ; analysis ; genetics ; Nuclear Proteins ; Promyelocytic Leukemia Protein ; RNA, Messenger ; analysis ; Transcription Factors ; analysis ; genetics ; Tumor Cells, Cultured ; Tumor Suppressor Proteins