Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21)

Abstract

The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML‐M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60‐kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90‐kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)‐positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150‐kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150‐kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)‐positive MDS/AML. Genes Chromosomes Cancer 27:229–238, 2000. © 2000 Wiley‐Liss, Inc.

Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation

“…EVI1 (also called PR domain member 3 or PRDM3) is a zinc-finger transcription factor and belongs to the PRDI-BF1-RIZ1 homologous (PR) domain family (Morishita, 2007). We previously identified the MDS1/ EVI1-like gene 1 (MEL1) as a member of the EVI1 gene family and also as a PR domain family member (PRDM16); this gene is located near the chromosomal breakpoint at chromosome 1p36 of t(1;3)(p36;q21) (Mochizuki et al, 2000;Shimizu et al, 2000). PRdomain deficient forms of EVI1 and MEL1 (MEL1S) are upregulated in both types of leukemia (Mochizuki et al, 2000;Nishikata et al, 2003).…”

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

“…In both cases, expression of PRDM16 is altered, either as a consequence of its juxtaposition to the enhancer element of RPN1 at 3q21 (10,11) or to its fusion with AML1 (AML1/PRDM16) at 21q15 (12)(13)(14). AMLs carrying t(1;3)(p36;q21) translocations present with a characteristic disease phenotype of trilineage dysplasia, dysmegakaryocytopoiesis, normal to elevated platelet counts, poor response to chemotherapy, and poor prognosis (15).…”

FISH analysis of hematological neoplasias with 1p36 rearrangements allows the definition of a cluster of 2.5�Mb included in the minimal region deleted in 1p36 deletion syndrome

“…Nine recurrent balanced rearrangements have been reported involving band 1p36 in hematological neoplasias, the most frequent being t(1;3)(p36;q21), which shares, with 3q21q26 syndrome, its association with myeloid malignancies and, in some cases, similar clinicopathological features (Shimizu et al 2000;Mitelman et al 2003;Lahortiga et al 2004). Moreover, loss of heterozygosity (LOH) of the 1p36 region has been reported in 47% of the patients with chronic myelocytic leukemia (CML) in transformation, in 30% of the patients with progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML), and in 13% of patients with MDS (Mori et al 1998(Mori et al , 2003Hofmann et al 2001).…”