| Disease |
Chronic myelogenous leukemia in blast crisis (BC-CML), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). |
| Note |
Cases of t(3;21)(q26;q22) are mostly treatment-related blast crises of CML, and treatment-related MDS/AMLs. However, the t(3;21) may also be found in rare instances of CML prior to the onset of blast crisis (Coyle and Najfeld, 1988).
In selected publications (Sacchi et al., 1994; Secker-Walker et al., 1995; Jeandidier et al., 2006; Poppe et al., 2006; Yin et al., 2006; see below), there were equal numbers of BC-CML cases and MDS/AML cases (53% and 47% respectively, out of 60 cases). A very few cases of chronic myeloproliferative disease without a t(9;22) have been documented (3,4% of the 146 cases of t(3;21) collected in the Mitelman database). Most cases of AML are M2-AML or M4-AML (+ two cases of M5b, one M6, one M7). MDS cases are mostly refractory anemia with excess of blasts (RAEB, also including RAEB-1 and RAEB-2) (+ one case of refractory anemia, one case of chronic myelomonocytic leukemia).
Cases of t(3;21) herein reviewed were selected and pooled together from the large studies (Lafage-Pochitaloff-Huvalé et al., 1989; Rubin et al., 1990; Sacchi et al., 1994; Secker-Walker et al., 1995; Jeandidier et al., 2006; Poppe et al., 2006; Lugthart et al., 2010; Paquette et al., 2011); BC-CML cases and MDS/AML cases were separated into two distinct entities for further studies; each entity was then compared with the equivalent entities from the largest study (Yin et al., 2006), and, in the occurence where there was no discrepancy, all the cases in each entity (BC-CML and MDS/AML) were again pooled together. As a matter of fact, the only discrepancy was the sex ratio in MDS/AML entity: 55% male / 45% female patients in the 29 cases from the "large studies" vs 30% male / 70% female patients in the 10 cases from the "largest study". In the review herein below, we therefore study a sample of 42 cases of BC-CML, and 39 cases of MDS/AML. In some instances, the whole sample of cases of t(3;21) harvested in the Mitelman database was taken into account (146 cases). |
| Etiology | Rubin et al., 1990 noted that t(3;21) represents 3,6% of therapy related MDS/AMLs (t-MDS/AML); they did not find one case of t(3;21) amongst 1500 de novo MDS/AMLs.
Yin et al., 2006 noted that 15 of their 16 BC-CML patients had previously been treated with hydroxyurea, before blast crisis. The occurrence of the t(3;21) heralded blast transformation. The authors conclude that prior treatment with hydroxyurea or other antimetabolites (fludarabine, 5-fluorouracil) are implicated in t(3;21) malignant blood diseases. Paquette et al., 2011, report that MECOM (also known as EVI1) translocations were seen in 12% of BC-CML before tyrosine kinase inhibitors treatments, a percentage reaching 35-40% with current treatments. The authors note that BCR-ABL1 and MECOM collaborate in leukemogenesis in animal models. Coexistence of BCR-ABL1 and MECOM translocation is sufficient to cause evolution towards BC-CML. The interval between the diagnosis of the initial neoplasm and the occurrence of the t(3;21) was 24 months (median, range 3-154 months) in CML-->BC-CML, and 38 months (median, range 6-144 months) for MDS/AML cases (Yin et al., 2006).
In our meta-analysis, 81% of 33 cases of BC-CML and 87% of 31 cases of MDS/AML can be considered to be secondary to previous treatment.
Results presented herein can be compared with those of a study from an International Workshop on treatment related leukemia: "t(3;21)(q26;q22) in treatment related leukemia". |
| Epidemiology | Translocation t(3;21) represents 0,14% of AML cases and 3% of 3q abnormalities cases (9 cases out of 6515 AML patients) in Lugthart et al., 2010.
Median age was 58 years (range 21-77) in BC-CML (n=42), and around 65 years (range 13-76, only one child) in MDS/AML (n=39).
From 146 cases extracted from the Mitelman database, sex ratio was 1,44 (59% male and 41% female patients). In the 42 cases of BC-CML herein selected for study, there was 71% male and 29% female patients (p<0.01). In the 39 cases of MDS/AML, no conclusion can be drawn, owing to conflictory data between "large studies" and "the largest study" (see above); the oddity of pooling heterogenous samples would result, in the present case, in a balanced sex ratio (19M/20F), but, again this is nonsense and the issue rewards further studies. |
| Cytology | Secker-Walker et al., 1995 noted low platelet counts, dysmyelopoiesis, decreased number of megakaryocytes, and micromegakaryocytes in MDS/AML cases; micromegakaryocytes were also seen in BC-CML cases (Yin et al., 2006). |
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| Prognosis | Poor survival (see figure above). Median survival is 4 months (range 0-21 months, n=18) in the MDS/AML group, and 9 months (range 1-79+ months, n=30 cases, reports from 1995 to 2011) in the BC-CML group. Median survival was 13 months in the most recent cases of BC-CML (n= 20 cases) (Yin et al., 2006; Paquette et al., 2011). |
| Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis. |
| Coyle T, Najfeld V. |
| Am J Hematol. 1988 Jan;27(1):56-9. |
| PMID 3162646 |
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| t(3;21)(q26;q22) in treatment related leukemia. |
| Huret JL. |
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| Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogenetique Hematologique. |
| Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Herens C, Michaux L, Verellen-Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Perot C, Van den Akker J, Gregoire MJ, Jonveaux P, Baranger L, Eclache-Saudreau V, Pages MP, Cabrol C, Terre C, Berger R; Groupe Francais de Cytogenetique Hematologique (GFCH). |
| Cancer Genet Cytogenet. 2006 Apr 1;166(1):1-11. |
| PMID 16616106 |
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| Translocation (3;21) in Philadelphia positive chronic myeloid leukemia: high resolution chromosomal analysis and immunological study on five new cases. |
| Lafage-Pochitaloff-Huvale M, Sainty D, Adriaanssen HJ, Lopez M, Maraninchi D, Simonetti J, Mannoni P, Carcassonne Y, Hagemeijer A. |
| Leukemia. 1989 Aug;3(8):554-9. |
| PMID 2747289 |
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| Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. |
| Lugthart S, Groschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Kohne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Dohner K, Lowenberg B, Dohner H. |
| J Clin Oncol. 2010 Aug 20;28(24):3890-8. doi: 10.1200/JCO.2010.29.2771. Epub 2010 Jul 26. |
| PMID 20660833 |
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| Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors. |
| Paquette RL, Nicoll J, Chalukya M, Elashoff D, Shah NP, Sawyers C, Spiteri E, Nanjangud G, Rao PN. |
| Cancer Genet. 2011 Jul;204(7):392-7. |
| PMID 21872826 |
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| EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. |
| Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. |
| Genes Chromosomes Cancer. 2006 Apr;45(4):349-56. |
| PMID 16342172 |
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| t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. |
| Rubin CM, Larson RA, Anastasi J, Winter JN, Thangavelu M, Vardiman JW, Rowley JD, Le Beau MM. |
| Blood. 1990 Dec 15;76(12):2594-8. |
| PMID 2265251 |
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| AML1 fusion transcripts in t(3;21) positive leukemia: evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AML1 transcripts. |
| Sacchi N, Nisson PE, Watkins PC, Faustinella F, Wijsman J, Hagemeijer A. |
| Genes Chromosomes Cancer. 1994 Dec;11(4):226-36. |
| PMID 7533526 |
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| Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study. |
| Secker-Walker LM, Mehta A, Bain B. |
| Br J Haematol. 1995 Oct;91(2):490-501. |
| PMID 8547101 |
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| MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1). |
| Wieser R. |
| Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):306-310. http://documents.irevues.inist.fr/bitstream/handle/2042/38551/12-2007-EVI103q26ID19.pdf?sequence=2 |
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| t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. |
| Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D. |
| Cancer. 2006 Apr 15;106(8):1730-8. |
| PMID 16532439 |
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