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CORRESPONDENCE Chronic myeloid leukemia (CML) is caused by a t(9;22)(q34;q11)
reciprocal translocation that generates a BCR-ABL
fusion gene on the 22q- or Philadelphia (Ph) chromosome and an
ABL-BCR gene on 9q+.1,2 Large deletions
adjacent to the t(9;22) breakpoint on the derivative 9q+ chromosome
have now been found, which result in genomic loss at both sides of the
translocation breakpoint.3,4,5,6 Recently, Huntly et
al7 analyzed a large series of CML patients and confirmed
that these deletions identify a subgroup of patients with relatively
poor prognosis. However, the molecular basis of this survival
disadvantage has not been identified. Due to its unique location
spanning the chromosome 9/chromosome 22 junction, ABL-BCR
appears as the most likely candidate for this role for the following
reasons: (1) it occupies the minimal region of deletion in the reported
cases6; (2) it is a "single-allele" gene whose deletion would result directly in total absence of the gene product, without a need to invoke a second event in a "2-hit"
model8; and (3) it is known not to be expressed in
approximately one third of CML patients,2,9 a frequency
similar to that found for the 9q+ deletions.6 To investigate this hypothesis, we performed reverse
transcription-polymerase chain reaction (RT-PCR) amplification
of the BCR-ABL and ABL/BCR genes in a
total of 519 patients (344 from the German CML studies III or
IIIA10 and 175 from the Hammersmith Hospital) diagnosed
with BCR-ABL-positive CML between December 1981 and
December 2000. The entire group comprised 319 males and 200 females
with a median age of 50.6 years (range, 12.4-83.2). After diagnosis,
patients were treated with either interferon- We analyzed a representative sample of 24 BCR-ABL-positive cases by fluorescence in situ hybridization (D-FISH) with commercially available BCR and ABL probes (Vysis, Richmond, UK), as described by Huntly et al.7 Eleven of the 24 patients were ABL-BCR positive, exhibited a classical t(9;22) and, as expected, did not have a 9q+ deletion. The remaining 13 patients did not express ABL-BCR and comprised 9 Ph-positive patients, 1 Ph-negative patient, and 3 patients with complex translocations. Only 7 of the 13 (54%) ABL-BCR-negative cases had a deletion: in 3 of these, both chromosome 9- and 22-derived material was missing, 3 had only chromosome 9-derived material missing, and one lacked exclusively chromosome 22-derived material. These results show that the overall correlation between ABL-BCR expression and deletion at the 9q+ derivative is relatively poor, with 6/24 (25%) cases being discordant. We next assessed whether ABL-BCR expression could influence
survival. A total of 471 patients with more than 30 days of follow-up after diagnosis were eligible for analysis. Probability of survival at
5 years was 51.8% (95% confidence interval [CI], 43-60) in the
ABL-BCR-negative group (n = 224) and 57.6% (95% CI,
49-66) in the positive group (n = 247, P = .49) (Figure
1). There were no differences between the
ABL-BCR-positive and -negative patients with regard to
gender, age, type of BCR-ABL transcript, treatment modality,
and Sokal13 or Hasford14 score. Likewise, no
significant difference in survival was observed between patients with
b3a2 and b2a2 BCR-ABL transcripts or between
ABL-BCR 1bb3 and 1bb4.
These results show that lack of ABL-BCR expression does not correlate with the presence of large deletions on the 9q+ derivative or with a shorter survival in CML patients. Since the powerful negative prognostic value of the 9q+ deletion has been confirmed in Huntly et al's7 large series of patients, it must be assumed that the molecular basis of the survival disadvantage lies in the loss of another gene(s) within the deleted region. However, as the extent and location of the deletion is rather variable, with some patients lacking material derived from either chromosome 9 or 22, it is possible that the group of patients with the 9q+ deletion is still heterogeneous and may encompass subgroups with variable survival disadvantage depending on the specific gene deleted during the translocation. As ABL-BCR has been eliminated as the most likely candidate for the prognostic value of the 9q+ deletion, attention should now be focused on genes surrounding the chromosome 9/chromosome 22 junction.
Josu de la Fuente, Kirsten Merx, E. Joanna Steer, Martin Müller, Richard M. Szydlo, Ole Maywald, Ute Berger, Rüdiger Hehlmann, John M. Goldman, Nicholas C. P. Cross, Junia V. Melo, Andreas Hochhaus, and the German CML Study Group Supported by grants from the Leukaemia Research Fund, United Kingdom (J.E.S., J.M.G., N.C.P.C., J.V.M.); the German Competence network "Acute and chronic leukemias"; and the Deutsche José-Carreras-Stiftung, Germany (K.M., M.M., O.M., U.B., R.H, A.H.) References
1.
Deininger MW, Goldman JM, Melo JV.
The molecular biology of chronic myeloid leukemia.
Blood.
2000;96:3343-3356
2.
Melo JV, Gordon DE, Cross NC, Goldman JM.
The ABL-BCR fusion gene is expressed in chronic myeloid leukemia.
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3.
Grand F, Kulkarni S, Chase A, Goldman JM, Gordon M, Cross NC.
Frequent deletion of hSNF5/INI1, a component of the SWI/SNF complex, in chronic myeloid leukemia.
Cancer Res.
1999;59:3870-3874 4. DeWald GW, Wyatt WA, Silver RT. Atypical BCR and ABL D-FISH patterns in chronic myeloid leukemia and their possible role in therapy. Leuk Lymphoma. 1999;34:481-491[Medline] [Order article via Infotrieve]. 5. Herens C, Tassin F, Lemaire V, et al. Deletion of the 5'-ABL region: a recurrent anomaly detected by fluorescence in situ hybridization in about 10% of Philadelphia-positive chronic myeloid leukaemia patients. Br J Haematol. 2000;110:214-216[CrossRef][Medline] [Order article via Infotrieve].
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Blood.
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Huntly BJP, Reid A, Campbell LJ, et al.
Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and represent the most powerful current prognostic indicator in chronic myeloid leukemia.
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Knudson AG Jr.
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1971;68:820-823 9. Melo JV, Hochhaus A, Yan XH, Goldman JM, et al. Lack of correlation between ABL-BCR expression and response to interferon-alpha in chronic myeloid leukaemia. Br J Haematol. 1996;92:684-686[CrossRef][Medline] [Order article via Infotrieve]. 10. Hehlmann R, Berger U, Hochhaus A, et al. Genetic randomization of allogeneic BMT vs. drug treatment in chronic myelogenous leukemia: the German CML study III [abstract]. Blood. 2000;96:141a. 11. Cross NC, Melo JV, Feng L, Goldman JM. An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia. 1994;8:186-189[Medline] [Order article via Infotrieve].
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Diamond J, Goldman JM, Melo JV.
BCR-ABL, ABL-BCR, BCR, and ABL genes are all expressed in individual granulocyte-macrophage colony-forming unit colonies derived from blood of patients with chronic myeloid leukemia.
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Hasford J, Pfirrmann M, Hehlmann R, et al.
A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.
J Natl Cancer Inst.
1998;90:850-858 15. Melo JV. BCR-ABL gene variants. Baillieres Clin Haematol. 1997;10:203-222[Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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and/or other
chemotherapy (n = 399), stem cell allograft (n = 100), or autograft
(n = 20). RT-PCR amplifications were done as previously
described.
