Case presentation

Case 1

A 62-year old man presented with shortness of breath and routine blood testing showed anaemia. He was a heavy smoker for 20 - 30 years and was diagnosed with chronic obstructive airways disease three years prior to presentation. Physical examination was unremarkable.

Complete blood counts showed: Hb 8.2 g/dL, white cell count 5.7 X 10⁹/L (differential count: neutrophils 67%, lymphocytes 28%, monocytes 4% and eosinophils 1%) and platelet count 195 X 10⁹/L. Peripheral blood film showed numerous giant platelets (Figure 1), bare nuclei and megakaryocyte cytoplasmic fragments (Figure 2). Occasional nucleated reds were found but there was no circulating blast cell.

Bone marrow examination showed normocellular marrow with increased blastic component to 13% (Figure 3). Blast cells are large in size and morphologically undifferentiated. Granulocytic maturation was evident. Erythroid activity was reduced and showed moderately dyserythropoietic features in terms of nuclear irregularities and binucleation. Megakaryocytes however were frankly dysplastic, showing multiple separated nuclei (Figure 4). Micromegakaryocytes (Figure 5) were also encountered. Stainable iron was increased but no ringed sideroblast was seen. The picture was consistent with a diagnosis of myelodysplastic syndrome, refractory anaemia with excess blasts-2 (RAEB-2) in accordance with WHO classification. Cytogenetics study of bone marrow cells showed: 46,XY,t(1;3)(p36;q21)[6]/46,XY[2] (Figure 6).

The patient was managed conservatively. One year after diagnosis, the peripheral blood picture became leucoerythroblastic and circulating blasts increased to 9 - 10%, suggestive of leukaemic transformation. Trephine biopsy showed marked marrow fibrosis and increased immature precursors. Low dose cytosine arabinoside treatment was administered without response. There was progressive thrombocytopenia and the patient died of disease 18 months after initial diagnosis.

Case 2

A 47-year old woman complained of dizziness. She was a non-smoker and non-drinker who enjoyed good past health. Physical examination was unremarkable.

Complete blood counts showed: Hb 9.6 g/dL, MCV 121 fL, white cell count 5.8 X 10⁹/L and platelet count 121 X 10⁹/L. Peripheral blood film examination showed macrocytic red cells and giant platelets (Figure 7). Occasional nucleated red cells were found but no blast cell was noted.

Bone marrow examination showed a normocellular marrow with increased blasts to 26% of all nucleated cells (Figure 8). Granulocytic series was relatively preserved and showed subtle dysplastic features. Megakaryocytes were frankly dysplastic and micromegakaryocytes were frequently encountered (Figure 9). Erythroid activity was marked reduced. Iron store was normal and no ringed sideroblast was seen. The picture was that of myelodysplastic syndrome (RAEBt) in FAB classification but was consistent with acute myeloid leukaemia (AML) with maturation in WHO classification. Cytogenetics study of bone marrow cells showed the following karyotype: 46,XX,t(1;3)(p36;q21)[10] (Figure 10).

The patient received an HLA-matched sibling transplant five months after diagnosis that was complicated by graft failure. A second transplanted resulted in engraftment, but was complicated by acute GVHD and recurrent infection. She developed convulsions and computed tomography of the brain showed multiple hypodense lesions at the white matter of bilateral occipital and parietal lobes extending to the vertex of the cerebrum. Treatment for suspected thrombotic thrombocytopenic purpura (TTP) was instituted without respond, and the patient eventually succumbed to disseminated aspergillus infection.

Discussion

Translocation (1;3)(p36;q21) was a rare but recurrent cytogenetic abnormality associated with the myeloid malignancies. A survey of Mitelman Database showed 46 cases, including 28 cases of acute myeloid leukaemia (AML) and 13 cases of myelodysplastic syndrome (MDS). Among AML there was a preponderance of acute myelomonocytic leukaemia (AML-M4), with a total of 14 cases. In 29 cases out of 46 (63%), the translocation occurred as a sole abnormality.

Typical patients with t(1;3)(p36;q21) were middle aged and severely anaemic, with frequent red cell macrocytosis. A characteristic feature is the normal to high platelet count. Bone marrow showed trilineage dysplasia but dysmegakaryocytopoiesis is the single most striking feature, as described for the present two cases. Although the disease may initially present as MDS, transformation to apparently refractory AML rapidly occurs. The prognosis is poor: analysis of 16 cases shows a median survival of 6 months for AML and 20 months for MDS. The dysmegakaryocytopoietic feature and involvement of chromosome 3q21 lead to the contention that t(1;3)(p36;q21) may be a variant of the so-called 3q21q26 syndrome that usually manifests as inv(3)(q21q26) and t(3;3)(q21;q26).

The chromosomal breakpoints at 3q26 in 3q21q26 syndrome are clustered at the 5' region of the EVI1 gene. On the other hand, the breakpoints at 3q21 are clustered within a 50 kb region near the ribophorin I (RPN1) gene, a member of the rough endoplasmic reticulum membrane proteins. It is suggested that the region of 3q21 with the RPN1 gene when translocated to the 3q26 region may activate EVI1 expression as an enhancer element.

More recently, the breakpoint at 1p36.3 of t(1;3)(p36;q21) was located within a 90 kb region, and subsequently a novel gene was identified at this region that encodes a zinc finger protein that is highly homologous to the MDS1/EVI1 gene, designated as MEL1 (MDS1/EVI1-like gene 1). The MEL1 gene is expressed in leukaemia cells with t(1;3) but not in other cell lines or normal bone marrow, spleen and fetal liver, suggesting that MEL1 expression is specific for t(1;3) positive MDS/AML. Due to positional relationship between the MEL1 as well as EVI1 genes and the fusion partner segment in each rearrangement, it is suggested that both genes are transcriptionally activated by translocation to the 3q21 region harbouring the RPN1 gene. Furthermore, because of the transcriptional activation of the EVI1 gene family members in both 3q21q26 syndrome and t(1;3) positive MDS/AML, they may share a common molecular mechanism for leukaemic transformation.

References

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Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 96: 3209 - 3214; 2000.

Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21 and 3q26 in myeloid malignancies: a United Kingdom Cancer Cytogenetic Group study. Br J Haematol 91: 490 - 501; 1995.

Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T, Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K. Genes Chromosomes Cancer 27: 229 - 238; 2000.