FCHSD2 predicts response to chemotherapy in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) is characterized by the growth and accumulation of cells blocked in their ability to differentiate, and blocks production of normal blood cells. The response to induction chemotherapy is heterogeneous, therefore biomarkers that predict for the outcome of such treatment are of potential value. FCHSD2 in a sensitized screen was identified as a potential chemo-protector (TW Mak, unpublished). In the present study, we found that FCHSD2 knockdown by shRNA could enhance chemosensitivity of U937 cells. This coincided with the increased expression of p21 and PUMA as well as the decreased expression of Bcl-2, c-myc and hTERT. In contrast, over-expression of FCHSD2 significantly increased cellular chemoresistance. To see if there was potential clinical relevance of FCHSD2 expression in leukemia we used qRT-PCR to assess FCHSD2 expression levels in peripheral blood or bone marrow blasts of 71 AML patients. There was an inverse correlation between the level of FCHSD2 with overall survival time (r=-0.7647, p<0.0001) and relapse free time (r=-0.8165, p<0.0001). By dividing patients into high and low expression groups using a FCHSD2 expression threshold value of 0.001, the median survival of the high expression group (72 days) was shorter than in the low expression group (2472 days). The average FCHSD2 expression level in 41 patients with complete remission was significantly lower than that in 30 non-responder patients (p<0.0001). Moreover, in 32 de novo AML patients receiving initial remission-induction chemotherapy, we confirmed that the patients with lower FCHSD2 expression prior to the treatment had an increased chance of attaining remission compared to patients with high level FCHSD2. In conclusion, our study, for the first time, demonstrates FCHSD2 as a predictor of outcome for AML patient. The determination of FCHSD2 expression at the time of diagnosis could help to identify the responses of AML patients to chemotherapy.
Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada.
Youqi
Y
Han
Jie
J
Cui
Yan
Y
Lu
Stephanie
S
Sue
Enrico
E
Arpaia
Tak W
TW
Mak
Mark D
MD
Minden
D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C479761:FCHSD2 protein, human; D008565:Membrane Proteins