Final Diagnosis -- Acute Lymphoblastic Leukemia with t(9;22)( q34;q11.2)



Examination of metaphase cells using classical trypsin-Giemsa banding cytogenetic techniques demonstrated the Philadelphia (Ph) chromosome in a single cell in a case of acute lymphoblastic lymphoma in an adult. Subsequent examination of interphase cells using Fluorescence In Situ Hybridization (FISH) confirmed the chromosome abnormality t(9;22)(q34;q11.2) with the associated BCR/ABL gene fusion in 92.5% of 200 examined interphase cells.

This translocation is most frequently associated with the clinical features of CML, and is noted in about 95% of cases, although detailed analysis using other methods, such as FISH, can confirm an occult BCR/ABL fusion despite lack of karyotypic abnormalities.[1] The Ph chromosome is also found in about 20% of adult ALL patients, predominantly those with immature B-cell differentiation markers or dual lymphoid and myeloid markers. This is not surprising, given the recent data confirming the presence of the BCR/ABL fusion product and the corresponding translocation in all three hematopoietic cell lines and B and T lymphocytes. Initial translocations in an early marrow precursor cell is suspected.[2] Ph-positive ALL in adults is associated with a poor prognosis and despite high remission rates comparable to those of Ph-negative ALL patients, remission duration and survival times were short (less than one year) [3].

The (9;22)(q34;q11.2) translocation results in the transfer of the ABL oncogene from chromosome 9q34 to the BCR (breakpoint cluster region) gene on chromosome 22q11.2. This leads to the formation of a fusion gene and production of an abnormal protein with increased tyrosine kinase activity. The latter plays a role in the malignant transformation of hematopoietic cells [4]. Recent studies have attempted to link the formation of slightly different breakpoints in the BCR/ABL genes to differing phenotypes and aggressive features of leukemic disease. One such study demonstrated two varying breakpoints, one of which produced a 210 kilodalton fusion protein of BCR/ABL, and the other, 190 kD; of these, the smaller of the two proteins was shown to have an enhanced transforming ability of lymphoid cells and thus may give rise to a more rapidly growing and progressive clone.[5,6]. Quanititative differences in protein expression (mosaicism for one or several variant BCR/ABL transcripts) may also play a significant role in this regard.[7]

The use of FISH to detect BCR/ABL translocations has gained favor in recent years; the probes have been approved by the Food and Drug Administration for use in diagnosis, provided that a standard cytogenetic analysis is also performed. It is critical to carry out classical cytogenetic analysis as well as FISH to rule out other alterations and/or those changes that herald the onset of blast crisis. FISH has demonstrated reliability and specificity when used in conjunction with classical cytogenetic karyotypic analysis, particularly when large numbers of cells need to be analyzed (i.e., for the purposes of detecting leukemic relapse or small subclones which may herald disease progression)[8]. In fact, a recent study demonstrated that FISH had superior sensitivity to standard cytogenetic analysis in detection of BCR/ABL translocations in chronic myelogenous leukemia patients by allowing analysis of larger numbers of metaphase (p<.0002) and interphase (p<.003) cells which might carry the translocation; this sensitivity may prove to be of great importance in the detection of minimal residual disease in these groups.[9]


  1. Cox MC, Maffei L, Buffolino S, Del Poeta G, Venditti A, et al. A comparative analysis of FISH, RT-PCR, and cytogenetics for the diagnosis of bcr-abl-positive leukemias. Am J Clin Pathol 1998; 109(1): 24-31.
  2. Haferlach T, Winkemann M, Nickenig C, Meeder M, Ramm-Petersen L, Schoch R, et al. Which compartments are involved in Philadelphia-chromosome positive chronic myeloid leukaemia? An answer at the single cell level by combining May-Grünwald-Giemsa stainingand fluorescence in situ hybridization techniques. Br J Hematol 1997; 97: 99-106.
  3. Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. [Review] Blood 1998; 91(11):3995-4019.
  4. Gorska-Flipot I, Norman C, Addy L, Minden M. Molecular pathology of chronic myelogenous leukemia. Tumour Biol 1990; 11 Suppl 1:25-43.
  5. Lugo TG, Pendergrast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science 1990; 247: 1079.
  6. McLaughlin J, Chianese E, Witte ON. Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. Mol Cell Biol 1989; 9: 1866-74.
  7. Saglio F, Pane F, Martinelli G, Guerrasio A. BCR/ABL transcripts and leukemia phenotype: an unsolved puzzle. Leuk Lymph 1997; 26: 281-286.
  8. Nolte M, Werner M, Ewig M, Wasielewski RV, Wilkens L, et al. Fluorescence In Situ Hybridization (FISH) is a reliable diagnostic tool for detection of the 9;22 translocation. Leuk Lymph 1996; 22: 287-94.
  9. Garcia-Isidoro M, Tabernero MD, Garcia JL, Najera ML, Hernandez JM, et al. Detection of the Mbcr-abl translocation in chronic myeloid leukemia by Fluorescence In Situ Hybridization: Comparison with conventional cytogenetics and implications for minimal residual disease. Hum Pathol 1997; 28(2): 154-59.

Contributed by Kevin D. Horn, MD, Sandra Kaplan, MD, Susanne M Gollin, PhD and Sofia Shekhter-Levin, MD, PhD


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