Chronic myelogenous leukemia in blast crisis (BC-CML), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

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 a study of cases with 3q21 and/or 3q26 abnormalities (Lugthart et al., 2010), no mutation of FLT3-TKD (tyrosine kinase domain), NPM1, CEBPA, KIT, MLL-PTD (partial tandem duplication), K-RAS were found in the t(3;21)(q26;q22) cases; in the whole 3q26 group (inv(3)/t(3;3) excluded), there were 11% of FLT3-ITD (internal tandem duplication) and 25% of N-RAS mutation.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).

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".

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

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).

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).

Breakpoint after exon 5 or 6 in RUNX1. Breakpoints are variable and dispersed along EVI1, MDS1 and the telomeric region of these two genes (Poppe et al., 2006).

Fusion gene: on the der(3); 5 RUNX1 - 3 MECOM.RUNX1/MECOM: 180 kDa. The translocation protein includes the N-term RUNX1 with the Runt domain and most of the gene MECOM, from the second untranslated exon of EVI1 to C-term, which includes the 2 zinc finger motifs, the repression domain, and the acidic domain, or also including the MDS1 PR domain followed by EVI1 domains as noted above.

Inappropriate and ectopic expression of MECOM (either as EVI1 or as MDS1-EVI1) (Poppe et al., 2006; Lugthart et al., 2010); interferes with RUNX1 functions in a dominant negative manner.

RUNX1/MECOM RUNX1 (21q22.12) MECOM (3q26.2) M t(3;21)(q26;q22)|RUNX1/MECOM RUNX1 (21q22.12) MECOM (3q26.2) TF LAML