Laura Berchicci

NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

Background NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated. Methodology and Principal Findings Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the “5q- syndrome” but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p = 0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion. Conclusions and Significance NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML.

Sustained ventricular tachycardia in a thalidomide-treated patient with primary plasma-cell leukemia.

Background A 68-year-old man diagnosed with primary plasma-cell leukemia was given thalidomide maintenance treatment for his disease. He had previously failed induction therapy with cyclophosphamide, vincristine, adriamycin, and dexamethasone, but achieved complete remission after melphalan therapy. Multiple syncopal episodes started to occur during thalidomide treatment, and a Holter electrocardiogram showed multiple abnormalities, with an episode of sustained ventricular tachycardia.Investigations Blood tests, peripheral blood smear, bone-marrow biopsy and aspirate, Holter electrocardiogram.Diagnosis Sustained ventricular tachycardia possibly owing to thalidomide treatment.Management Thalidomide withdrawal, dexamethasone maintenance therapy, monthly oral courses of combined melphalan and prednisone, salvage therapy with bortezomib.

MN1-ETV6 fusion gene arising from MDS with 5q-.

An isolated 5q− Myelodysplastic Syndrome (MDS), “5q− synrome”, is characterized by a favorable prognosis whereas a eletion of chromosome 5q associated with one additional abnorality seems to confer a shorter median survival even though the rognostic impact of diverse aberrations in addition to 5q− has not een established [1]. Translocation t(12;22)(p13;q11)/MN1-ETV6 has been found in nly 2 cases of MDS [2,3]. The putative MN1-ETV6 transcription facor has transforming activity in vitro and may induce Acute Myeloid eukemia (AML) in mice [4,5]. Here we report the first case of MDS with 5q− and trisomy 21 t diagnosis which developed into secondary MN1-ETV6 positive ML.

A NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) without HOXC cluster gene involvement.

We report a case of adult acute myeloid leukemia with a new t(11;12)(p15;q13) underlying a NUP98 rearrangement without HOXC cluster gene involvement. We designed a specific double-color double-fusion FISH assay to discriminate between this t(11;12)(p15;q13) and those producing NUP98-HOXC11 or NUP98-HOXC13. Our fluorescence in situ hybridization (FISH) showed that putative candidate partners mapping 600 kilobases centromeric to HOXC were RARG (retinoic acid receptor gamma), MFSD5 (major facilitator superfamily domain containing 5), and ESPL1 (extra spindle pole bodies homolog 1). It is noteworthy that so far only ESPL1 has been implicated in human cancers. This FISH assay is useful for diagnostic screening of NUP98-positive leukemias.

FISH analysis reveals frequent co-occurrence of 4q24/TET2 and 5q and/or 7q deletions.

We investigated TET2 deletion in 418 patients with hematological malignancies. Overall interphase FISH detected complete or partial TET2 monoallelic deletion (TET2(del)) in 20/418 cases (4.7%). TET2(del) was very rare in lymphoid malignancies (1/242 cases; 0.4%). Among 19 positive myeloid malignancies TET2(del) was associated with a 4q24 karyotypic abnormality in 18 cases. In AML, TET2(del) occurred in CD34-positive hematopoietic precursors and preceded established genomic abnormalities, such as 5q- and -7/7q-, which were the most frequent associated changes (Fishers exact test P=0.000).