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Clinical Cancer Research Vol. 5, 4059-4064, December 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Significance of FHIT Expression in Chronic Myelogenous Leukemia

Hagop M. Kantarjian1, Moshe Talpaz, Susan O’Brien, Taghi Manshouri, Jorge Cortes, Francis Giles, Mary Beth Rios, Carlo M. Croce and Maher Albitar

Departments of Leukemia [H. M. K., S. O., J. C., F. G., M. B. R.], Hematopathology [T. M., M. A.], and Bioimmunotherapy [M. T.], M. D. Anderson Cancer Center, Houston, Texas 77030, and the Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania [C. M. C.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Loss or reduced expression of the fragile histidine triad (FHIT) gene, a tumor suppressor gene localized at chromosome 3p14.2, is common in several solid and hematological cancers and has been associated with tumor progression and worse prognosis. The role of the FHIT gene in the pathogenesis of chronic myelogenous leukemia (CML) or its progression from a chronic phase to the accelerated and blastic phases is not known. The aim of this study was to evaluate whether Fhit protein expression is altered in CML, and whether it plays any role in CML progression, disease responsiveness to therapy, or prognosis. A total of 195 patients with Philadelphia chromosome-positive CML were evaluated, including 129 patients in early chronic phase (time from diagnosis to study, 12 months or less), 30 patients in late chronic phase, and 36 patients in the accelerated and blastic phases. The levels of cellular Fhit protein expression were determined using Western blot analysis and solid-phase RIA and compared to the levels in 31 normal marrows. The median Fhit expression in normal marrows was assigned a value of 1, and the levels in CML samples were normalized to the median of the normal control. Fhit levels in CML samples were evaluated in relation to CML phase and patient characteristics and prognosis in the early chronic phase. The median Fhit value in CML samples was 0.89 (range, 0.34–2.62). Eight of the 195 (4%) CML samples showed Fhit levels <0.5 and lacked detectable Fhit protein by Western blot. There was no difference in the levels of Fhit expression by different CML phases. In early chronic phase, reduced Fhit expression tended to be associated with leukocytosis (P = 0.04) and lower platelet counts (P = 0.01), but not with poorer-risk groups. No differences in response to IFN-{alpha} therapy or in survival were observed by different Fhit levels. Lack of Fhit protein expression was detected in 4% of CML cases, and reduced expression occurred in a subpopulation of patients. However, reduced Fhit expression is not associated with progression, response to therapy, or prognosis in CML.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The FHIT gene located on chromosome 3p14.2 is a tumor suppressor gene that is deleted or inactivated in multiple human cancers. FHIT is believed to be a tumor suppressor gene, but its physiological function is still unknown (1) . Deletion of both alleles is the most frequent event, resulting in a loss of gene function (1) . Introduction of FHIT sequences into tumor cell lines suppressed their ability to form tumors in nude mice (2) . Homozygous deletions of the FHIT gene and absent or altered FHIT transcription are common in epithelial cancers such as lung (3, 4, 5) , breast (6) , head and neck (7) , esophageal (8) , gastric (9) , pancreatic (10) , renal (11) , prostate (12) , cervical (13 , 14) , and hepatic cancers (15) . Evidence suggests that FHIT exon deletion is a target of tobacco carcinogens and asbestos, placing it among the possible multistep events of lung cancer pathophysiology (16) .

Chromosome 3 abnormalities occur in a range of hematological cancers (17) , including leukemias (17) . Translocations involving 3p14 and loss of heterozygosity at 3p have been reported in CML2 (18) . Aberrant FHIT transcripts, in addition to the wild-type transcript, and infrequent total loss of FHIT RNA expression have been reported in acute and chronic leukemias (19, 20, 21, 22) . Fhit protein expression was found to be lost frequently in acute lymphocytic leukemia and suggested to be implicated in its pathophysiology.3

CML is a paradigm of a cancer with multistep disease evolution from chronic phase to the accelerated and blastic phases. The Ph abnormality and related molecular changes have been causally associated with disease initiation (23, 24, 25, 26) . However, the molecular events associated with disease progression have eluded identification thus far. Amplification of BCR-ABL, loss of p53, increased DNA and site-specific methylation (e.g., Pa methylation within BCR-ABL), multidrug resistance expression, enhanced BCL2 expression and reduced apoptosis, and involvement of p15/16 tumor suppressor genes have all been investigated (27, 28, 29, 30, 31, 32, 33, 34, 35) .

In this study, we investigated Fhit protein expression in Ph-positive CML and studied the significance of reduced Fhit protein expression on disease progression, disease aggressiveness, response to therapy, and survival.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Group.
Samples from 195 patients with Ph-positive CML entered on our studies were analyzed. Informed consent was obtained according to institutional guidelines. Patients were treated on programs approved by the Institutional Review Board. The characteristics of the study group are shown in Table 1.Citation One hundred and twenty-nine patients were in early chronic phase (time from diagnosis to analysis, <12 months), 30 patients were in late chronic phase, and 36 patients were in either the accelerated (25 patients) or blastic phase (11 patients). The criteria for CML accelerated or blastic phase were as described previously (36 , 37) . Seventy-four patients (35%) were females, and 42 patients (20%) were more than 60 years old. Thirty-one bone marrow samples from normal control patients being evaluated for metastatic solid tumors or lymphoma without evidence of tumors in the bone marrow were used to evaluate the levels of Fhit protein in normal marrows.


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  		Table 1 Characteristics of the study group (195 patients)

 
Extraction of Protein.
Total cellular protein was extracted from cells after lysing RBCs as described previously (38) . Briefly, cells were lysed in TENN buffer [50 mM Tris-HCI (PH 7.4), 5 mM EDTA, 0.5% NP40, and 150 mM NaCl supplemented with 1 mM phenylmethylsulfonyl fluoride, 2 µg/ml leupeptin, and 2 µg/ml pepstatin] for 30 min on ice with frequent vortexing and then left on ice for 1 h. Lysates were then microcentrifuged for 1 h at 14,000 rpm. Protein concentration was determined by the Bradford method, and 200 µg cell of extract were run on a 9.5% SDS-polyacrylamide gel and stained with Coomassie Blue R-250 to check the protein profile and accuracy of the determination of the amount of protein.

Immunoblot Analysis of Fhit Protein.
Cell extracts (200 µg) from CML patients and normal controls were electrophoretically separated on a 12.5% SDS-polyacrylamide gel and transferred to nitrocellulose paper overnight. The nitrocellulose membrane was blocked with 5% nonfat milk in PBS containing 0.1% Tween 20 and 0.01% sodium azide for 6–8 h at room temperature. The blot then was incubated overnight at 4°C with anti-Fhit polyclonal antibody (Zymed Laboratories, Inc., San Francisco, CA) diluted 1:1000 in PBS containing 2.5% BSA, 2.5% nonfat milk, and 0.01% Tween 20. The membrane was washed with PBS containing 0.01% Tween 20. The blot then was incubated with horseradish peroxidase antirabbit immunoglobulin antibody diluted 1:2000 in PBS containing 1% nonfat milk and 0.1% Tween 20. Immunoreactive bands were visualized with the enhanced chemiluminescence detection system (Amersham, Arlington Heights, IL). The membrane was then stripped under conditions recommended by the manufacturer and blocked and reprobed with mouse monoclonal anti-actin IgM antibodies (Amersham) to assure equal loading of the protein. The autoradiographs were scanned, and bands were quantified using Scan Analysis software from Biosoft (Cambridge, United Kingdom) and a Macintosh-based scanner and computer.

Solid-Phase Plate RIA.
Fhit protein was quantified by solid-phase plate RIA. The assay has been described previously in detail (38 , 39) . Briefly, RIA plates were coated overnight at 4°C with 5 µg of protein extracted from CML patients and normal individuals in 50 µl of PBS. The RIA plates were then washed with PBS and blocked with 100 µl of 1% BSA (Amersham) in PBS for 1 h at 37°C. The plates were incubated over night at 4°C with 50 µl of rabbit anti-Fhit antibody (Zymed Laboratories, Inc.) diluted 1:500 in PBS containing 1% BSA. The plates were then washed with PBS and amplified with goat antirabbit IgG antisera (Sigma Chemical Co.) diluted 1:500 in 0.1% BSA in PBS for 2 h at 37°C. After washing, plates were developed with excess 125I-labeled protein G [200,000 cpm (50 IU) of 0.1% BSA in PBS/well) for 2 h at room temperature, washed with PBS, and separated into individual wells, and the counts in each well were counted with a gamma counter (LKB Biotechnology, Uppsala, Sweden). The assays were performed in triplicate, and the results were corrected for the nonspecific binding (1–2%) detected in control wells that were not coated with a test antigen but blocked with BSA. The assay was also performed with antiactin antibodies to confirm complete and uniform coating of the surfaces of the plates.

RNA Isolation and Analysis.
Total RNA was extracted from various tissues of transgenic mice by the guanidine hydrochloride method, as described previously (40) . Fhit mRNA was analyzed using RT-PCR using primers 5'-ATGTCGTTCAGATTTGGCCAAC-3' and 5'-TCATAGATGCTGTCATTCCTGT-3'. The amplification product encompassed the beginning of the translation initiation site up to 340 bp of the Fhit cDNA. As a control to assure the viability of the mRNA, we amplified RAR-{alpha} using the primers 5'-CTCACAGGCGCTGACCCCAT-3' and 5'-TCCCCAGCCACCATTGAGACC-3', which amplify 151 bp of the RAR-{alpha} cDNA. Reverse transcription was carried out using the 3' primers as described previously (40) . PCR was carried out using the following cycling conditions: denaturation at 95°C for 5 min; followed by 30 cycles at 54°C for 1 min, 72°C for 1 min, and 94°C for 1 min. The amplification products were resolved on an agarose gel. The RT-PCR bands were scanned, and bands were quantified using Scan Analysis software from Biosoft and a Macintosh-based scanner and computer.

Statistical Considerations.
Comparisons among characteristics of subgroups were made using the {chi}2 test. Survival durations calculated by the Kaplan-Meier method and compared by the log-rank test (41 , 42) . Risk groups in early chronic phase CML were defined as described previously (43) . Analysis of Fhit expression was performed considering the values in different forms: (a) continuous; (b) quartiles; (c) above and below the median; and (d) <1 (the normalized value based on 30 normal controls).

Categorization of responses to IFN-{alpha} therapy was as described previously (44) . A CHR required normalization of peripheral blood counts with WBC <109/liter and no abnormal peripheral cells (blasts, promyelocytes, and myelocytes), a platelet count <450 x 109/liter, and disappearance of signs and symptoms of disease including palpable splenomegaly. Within CHR, a cytogenetic response was categorized as follows: (a) complete, Ph-positive cells reduced to 0% as the best response; (b) partial, Ph-positive cells reduced to 1–34%; and (c) minor, Ph-positive cells reduced to 35–90%. A major cytogenetic response included complete and partial response (Ph-positive <35%). A partial hematological response was as described for CHR, except for persistent immature peripheral cells or persistent splenomegaly or thrombocytosis, but at less than 50% of pretreatment levels.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
FHIT Expression and CML Phase.
Bone marrow samples from 31 normal individuals showed detectable levels of Fhit protein on Western blot (Fig. 1)Citation . To quantify the levels of Fhit protein expression, we used solid-phase RIA. The median CPM of 31 normal control bone marrows was assigned a value of 1, and the values of the CML samples were normalized to the median of the normal control. Minimal variation was observed between the normal controls (SD = 0.20). Eight of 195 (4%) CML samples showed Fhit levels <0.5 by RIA and no detectable Fhit protein on Western blot analysis (Fig. 1)Citation . Four patients (2%) showed relatively high levels of Fhit protein (>2; Fig. 1Citation ). All analyzed samples showed a single protein band of approximately Mr 17,000. No abnormal protein bands or alternatively spliced Fhit protein was detected on Western blot.



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  		Fig. 1. Representative example of Western blot analysis of Fhit protein. The filter was stripped and reprobed with actin antibody to confirm equal loading of the protein. Normal bone marrow sample is shown (Lane N). Some CML samples show undetectable levels of Fhit protein (Lanes 2, 7, and 13); two samples show increased levels of expression (Lanes 9 and 10).

 
To confirm the results of the Western blot analysis/RIA analysis, four samples were analyzed for the expression of Fhit mRNA (Fig. 2)Citation . Two of these samples showed a relatively high level of Fhit protein expression, one had normal expression, and one had no detectable Fhit level by Western blot. We used RT-PCR to detect Fhit mRNA. As expected, no detectable Fhit mRNA was seen in the sample that had not shown protein expression, and increased mRNA expression was seen in samples with relatively high expression (Fig. 2)Citation . We used RAR-{alpha} mRNA as an internal control to assure the use of equal amounts of mRNA.



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  		Fig. 2. RT-PCR results of Fhit mRNA (F) in four CML samples (1–4). Normal bone marrow was used as a control (C). Values from the RIA analysis of the Fhit protein are shown. An equal amount of mRNA was used to amplify RAR-{alpha} mRNA (R) to confirm the viability of the mRNA. The size marker (M) was HaeIII fragments of {phi}X174 plasmid.

 
Expression of cellular Fhit protein in different categories of CML patients is shown in Table 2Citation . The median value was 0.89. The median values did not differ by CML phases. No reduced FHIT expression was observed in CML progression to advanced phases (Table 2)Citation .


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  		Table 2 Fhit cellular protein expression by CML phase

 
FHIT Expression in Early Chronic Phase: Correlations and Prognosis.
Of 123 patients in early chronic-phase CML, 68 (53%) had Fhit levels <0.9. Patients with a reduced cellular Fhit expression tended to have a higher incidence of leukocytosis (P = 0.04) and a lower incidence of thrombocytosis (P = 0.01). They were not associated with a higher occurrence of poor-risk disease (Table 3)Citation .


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  		Table 3 Association of Fhit cellular protein expression with host and disease characteristics

 
A total of 113 patients in early chronic-phase CML received IFN-{alpha}-based therapy. No differences in response to therapy were observed by different Fhit expression (Table 4)Citation . Similarly, survival was not significantly different among patients with different levels of Fhit expression (Fig. 3)Citation .


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  		Table 4 Fhit expression and response to IFN-{alpha} therapy in early chronic phase CML (113 patients)

 


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  		Fig. 3. Survival in early chronic-phase CML by Fhit protein expression.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Abnormalities involving chromosome 3 occur in 10–20% of patients with CML disease clonal evolution; involvement of the 3p14.2 site is less common. However, it has recently been shown that cryptic cytogenetic abnormalities occur, which are detected at a high incidence at the molecular level and influence disease prognosis significantly. For example, whereas t(12;21) is rare in childhood acute lymphocytic leukemia (less than 1–2%), TEL gene rearrangement is observed in 25–30% of cases and is associated with favorable prognosis (45) . Similar observations were reported with loss of heterozygosity of the ataxia telangectasia gene in chronic lymphocytic leukemia (46) . Thus, the cytogenetic abnormalities may not always be adequate cytogenetic fingerprints for the underlying molecular abnormality. In fact, whereas double Ph, trisomy 8, and isochromosome 17 are frequent abnormalities with CML transformation (37 , 47) , they have not resulted (except for 17p and p53; Ref. 48 ) in the identification of specific molecular markers of CML evolution.

Events of cancer transformation may be shared steps in multiple cancers. This is the case with DNA methylation, p15/p16 abnormalities, multidrug resistance overexpression, loss of p53 tumor suppressor genes, RAS mutations, and many others. Because loss or reduced expression of FHIT, which is believed to be a tumor suppressor gene, has been documented to involve and influence the outcome of a broad range of solid and hematological cancers, it was appropriate to investigate its expression and significance in CML more thoroughly (22) . This was also compelling because the molecular mechanisms underlying progression of CML from chronic phase into transformed phases have not been well elucidated. Identifying such mechanisms of transformation could allow us to develop therapeutic modalities that may prevent CML transformation and maintain the disease in chronic phase, thus improving prognosis. This would be analogous to polycythemia vera and essential thrombocytosis, where the incidence of spontaneous transformation is less than 5%, and, consequently, the 10-year-survival rates are 60–70%. This is in contrast to CML, where transformation occurs in 85% of patients, and the median survival is only 5–6 years.

The FHIT gene is a large gene (1 Mb) and is difficult to analyze. RNA quantification is also cumbersome and does not consider posttranscriptional mechanisms that may influence the final level of functional protein. Therefore, we analyzed the protein levels in CML samples. Our data demonstrate that a complete absence of Fhit protein occurs in 4% of cases. Cases that expressed <0.5 (less than 0.5 the level in normal marrow) by RIA showed no detectable protein on Western blot and were therefore considered to lack Fhit expression. Other cases showed various levels of Fhit deficiency that may represent heterozygous loss of expression or the presence of a subpopulation of cells that express normal levels of Fhit. This subpopulation may be normal cells or leukemic cells. Most importantly, our analysis did not support the hypothesis that FHIT is involved in CML evolution. Reduced Fhit protein expression was observed at similar rates in early chronic, late chronic, and accelerated/blastic phases. Whereas reduced Fhit expression in early chronic phase was associated with some adverse disease features (Table 3)Citation , it was not associated with disease resistance, because response to IFN-{alpha} therapy was similar among subgroups of patients with low or high Fhit expression (Table 4)Citation . Finally, reduced expression of Fhit did not herald a worse prognosis. Survival of patients was similar, regardless of whether the disease expressed low or high Fhit levels (Fig. 3)Citation .

In summary, our analysis does not support a role for FHIT, a tumor suppressor gene, in disease evolution in CML, nor does it suggest any significant association between reduced Fhit expression and disease aggressiveness, poor response to IFN-{alpha} therapy, or poor prognosis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Leukemia, Box 61, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Back

2 The abbreviations used are: CML, chronic myelogenous leukemia; Ph, Philadelphia chromosome; RT-PCR, reverse transcription-PCR; RAR, retinoic acid receptor; CHR, complete hematological response. Back

3 C. Halla, M. Albitar, J. Letofsky, M. J. Keating, K. Huebner, and C. M. Croce. Loss of FHIT expression in acute lymphoblastic leukemia, submitted for publication. Back

Received 5/ 4/99; revised 9/13/99; accepted 9/20/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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