Molecular responses during chemotherapy in acute myeloid leukemias in predicting poor-response to standard chemotherapy.
Signal transduction pathways are constitutively expressed in leukaemic cells resulting in aberrant survival of the cells. It is postulated that in cells of chemo-sensitive patients, chemotherapy induces apoptotic signals leading to cell death while survival signals are maintained in cells of chemo-resistant patients. There is very little information currently, on the expression of these mediators in patients immediately after chemotherapy initiation. We examined the expression pattern of proinflammatory cytokines, signaling molecules of the PI3K and MAPK pathways molecules and death receptor, DR5 on paired samples at diagnosis and during chemotherapy in acute myeloid leukaemia patients treated with cytosine arabinoside and daunorubicin. The results were correlated with remission status one month after chemotherapy. We found that in chemo-sensitive patients, chemotherapy significantly increased the percentage of cases expressing TNF-alpha (p = 0.025, n = 9) and IL-6 (p = 0.002, n = 11) compared to chemo-resistant cases. We also observed an increased percentage of chemo-sensitive cases expressing DR5 and phosphorylated p38, and Jnk. Thus, expression of TNF-alpha, IL-6, DR5, phospho-p38 and phospho-Jnk may regulate cell death in chemo-sensitive cases. In contrast, a significantly higher percentage of chemo-resistant cases expressed phospho-Bad (p = 0.027, n = 9). IL-beta and IL-18 were also found to be higher in chemo-resistant cases at diagnosis and during chemotherapy. Thus, expression of various cellular molecules in leukaemic blasts during chemotherapy may be useful in predicting treatment outcome. These cellular molecules may also be potential targets for alternative therapy.
Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor. maha@medic.upm.edu.my
Abdullah
A
Maha
Soon-Keng
SK
Cheong
Chooi-Fun
CF
Leong
Heng-Fong
HF
Seow
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D053492:Elafin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects*; D055815:Young Adult
D000970:Antineoplastic Agents; D016207:Cytokines; D053492:Elafin; C506806:PI3 protein, human; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003561:Cytarabine; D020928:Mitogen-Activated Protein Kinases; D003630:Daunorubicin