Subject(s)
Antineoplastic Agents/adverse effects , Hypercalcemia/chemically induced , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/adverse effects , Antineoplastic Agents/therapeutic use , Child , Diagnosis, Differential , Diphosphonates/therapeutic use , Headache/chemically induced , Humans , Hypercalcemia/diagnosis , Hypercalcemia/drug therapy , Male , Nausea/chemically induced , Remission Induction , Time Factors , Tretinoin/therapeutic useABSTRACT
We studied retrospectively the clinical feasibility of minimal residual disease (MRD) monitoring by reverse transcription-polymerase chain reaction (RT-PCR) detecting the PML/retinoic acid receptor alpha (RARalpha) chimeric gene in children with acute promyelocytic leukemia (APL). MRD monitoring of APL was performed with standard and nested RT-PCR for PML/RARalpha gene, the sensitivity of which was 1 leukemic cell in 10(3)-10(4) and 1 in 10(4)-10(5) cells, respectively. Patients were nine children with APL (average age: 8.3 year; average period of follow-up: 69.2 months) who, after achieving remission with all-trans retinoic acid (ATRA), received treatment either with multidrug chemotherapy or with a combination of chemotherapy and ATRA. Out of six patients treated with multidrug-combined chemotherapy, two patients exhibited PCR positivity after six months of post- remission therapy, which shifted from the detectable range of the nested PCR to that of the standard PCR. These two patients subsequently relapsed and, together with two of the other patients receiving multidrug-combined chemotherapy, underwent allogeneic bone marrow transplantation. No MRD was detected in these patients after transplantation. In the remaining three patients who underwent cyclic treatment with alternative chemotherapy and ATRA, two showed positive RT-PCR at the nested or standard level, respectively, after six months of combined therapy, and one of them relapsed. Overall, three of four patients with MRD detected in post-remission period ultimately relapsed, while all of five patients without detectable MRD had a good prognosis. These findings suggest that impending relapse may be predicted by the detection of preceding PCR positivity with an increasing quantity of the PML/RARalpha mRNA that appears beyond six months of post-remission chemotherapy, with or without combined ATRA therapy.
Subject(s)
Leukemia, Promyelocytic, Acute/genetics , Receptors, Retinoic Acid/genetics , Recombinant Fusion Proteins/genetics , Adolescent , Alleles , Bone Marrow/pathology , Child , Child, Preschool , DNA Primers , Female , Humans , In Situ Hybridization , Leukemia, Promyelocytic, Acute/pathology , Male , RNA, Messenger/analysis , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that regulates the proliferation, differentiation and survival of cells in the granulocytic lineage. In this study, however, we found that G-CSF or interleukin-6 (IL-6) induced UF-1, a human acute promyelocytic leukemia cell line, into apoptosis that was confirmed by morphological features and DNA fragmentation. This rare response is demonstrated for the first time with human acute promyelocytic leukemia cell line. The apoptosis induced by G-CSF or IL-6 was not preceded by terminal differentiation characterized by morphological maturation, capability to reduce nitroblue tetrazolium, or surface CD11b expression. Interestingly, Western blot analysis revealed that the stimulation of UF-1 with either G-CSF or IL-6 resulted in excessive activation of both signal transducer and activator of transcription 3alpha (Stat3alpha) and Stat3beta. Furthermore, an additional 18 kDa Bax-related protein was expressed by the stimulation of G-CSF or IL-6, while Bcl-2 and Bcl-X proteins remained unchanged. These findings suggest that UF-1 may be a valuable tool in investigating the aberrant regulation of apoptosis, especially the Stat3 involvement in the mechanism of apoptosis induction.
