Inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia

Metzler, Markus; Staege, Martin S.; Harder, Lana; Mendelová, Denisa; Zuna, Jan; Froňková, Eva; Meyer, Claus; Flohr, Thomas; Bednarova, D; Harbott, Jochen; Langer, Thorsten; Gesk, S; Trka, Jan; Siebert, Reiner; Dingermann, Theo; Marschalek, Rolf; Niemeyer, Charlotte M.; Rascher, Wolfgang

doi:10.1038/leu.2008.50

Cited by 19 publications

(21 citation statements)

References 8 publications

(8 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The (pre)leukaemic clonal dynamics described here are consistent with our observations in secondary leukemias, 5,6 and the fluctuation in the percentage of ETV6-RUNX1-positive cells detected by fluorescence in situ hybridization described in another ALL patient with a preleukemic phase. 7 This suggests that some immunological mechanisms might be capable of temporary surveillance over the pre-malignant clones, at least in some leukemia subtypes.…”

Section: 8supporting

confidence: 79%

Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance

Zimmermannová¹,

Žaliová

Moorman

et al. 2017

Haematologica

View full text Add to dashboard Cite

Section: 8supporting

confidence: 79%

Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance

Zimmermannová¹,

Žaliová

Moorman

et al. 2017

Haematologica

View full text Add to dashboard Cite

“…Robinson et al, (2008) reported a case in which etoposide associated MLL/FRYL clone, in a patient treated for neuroblastoma, was dominant in the bone marrow for 40 months prior to a diagnosis of myelodysplastic syndrome. Finally, we recently published two cases of secondary T-cell ALL with MLL/MAML2 rearrangement detectable before the diagnosis of the secondary leukemia (Metzler et al, 2008). One of the cases showed transient peak of MLL/MAML2 positive, Ig/TCR negative preleukemic population that comprised up to 10% of the bone marrow cells 15 months before the secondary T-ALL onset.…”

Section: Discussionmentioning

confidence: 99%

“…In these reports, no data were provided on additional genetic abnormalities that might have contributed to leukemogenesis (Leblanc et al, 1994;Megonigal et al, 2000;Blanco et al, 2001;Metzler et al, 2004;Ng et al, 2004;Takei et al, 2006;Nemoto et al, 2007;Metzler et al, 2008). In the case of secondary myelodysplastic syndrome (MDS) with MLL/FRYL fusion (Robinson et al, 2008), a subclonal presence of t(2;9) was detected in 0-6/20 mitoses in some samples preceding the secondary MDS and loss of chromosome 16 and add (18q) were shown 3 months before the evident secondary MDS diagnosis in 4 out of 17 t(4;11) positive cells.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of secondary or treatment related leukemias with MLL gene rearrangements are also characterized by a relatively short latency (Felix, 1998). On the other hand, in a few cases of secondary hematological malignancies with MLL gene fusions, it has been possible to backtrack the appearance of the MLL rearrangement to several months (up to more than 6 years) prior to diagnosis of secondary leukemia (Leblanc et al, 1994;Megonigal et al, 2000;Blanco et al, 2001;Metzler et al, 2004;Ng et al, 2004;Takei et al, 2006;Nemoto et al, 2007;Metzler et al, 2008;Robinson et al, 2008) (see Table 1). We report here a case of secondary, B-lineage acute lymphoblastic leukemia (ALL) with MLL/ FOXO3A fusion gene.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Covert preleukemia driven by MLL gene fusion

Zuna

Burjanivová

Mejstříková

et al. 2008

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Acute leukemia is considered to be a two-or multiple-step process. Although there is a considerable knowledge regarding the character of the ''first hit,'' the nature of the ''second hit'' remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential ''second hit'' precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.

show abstract

“…In addition, RT-PCR may be unsuitable for detecting the gene fusions when the amount of the fusion transcripts is significantly low. Furthermore, other translocations involving MAML2, such as the MLL-MAML2 fusion that has been reported in some hematopoietic malignancies, (14,15) have not been studied in mucoepidermoid carcinomas.In this study, we screened 95 mucoepidermoid carcinoma cases for CRTC1-MAML2 and CRTC3-MAML2 fusions by RT-PCR and for MAML2 gene rearrangement by FISH using an MAML2 break-apart probe. In addition, we examined MLL gene rearrangement in the CRTC1/3-MAML2-negative and MAML2 rearrangement-positive cases, and quantified the CRTC1-MAML2 fusion transcript in selected tumor cases.…”

mentioning

confidence: 99%

Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma

et al. 2012

View full text Add to dashboard Cite

CRTC1-MAML2 and CRTC3-MAML2 fusions have been associated with favorable clinicopathological features of mucoepidermoid carcinomas. However, the significance of the MAML2 gene split has not been fully clarified. In the present study, 95 mucoepidermoid carcinomas (paraffin-embedded materials) were analyzed for CRTC1-MAML2 and CRTC3-MAML2 fusions by RT-PCR and for the MAML2 gene split by FISH. Quantitative RT-PCR for the CRTC1-MAML2 transcript was performed in selected cases. MLL gene involvement, which has been reported in some leukemia cases, was examined by FISH in fusion partner-unknown cases. CRTC1-MAML2 and CRTC3-MAML2 fusions were detected in 37 and 6 cases, respectively. The MAML2 gene split was detected in 62 cases, which included all CRTC1/3-MAML2 fusion-positive cases. The level of CRTC1-MAML2 transcript expression was highly variable, and its clinicopathological impact was unclear. The MLL gene split was not detected. Mucoepidermoid carcinomas negative for CRTC1/3-MAML2 and positive for the MAML2 gene split (n = 19) showed favorable clinicopathological tumor features similar to those positive for CRTC1/3-MAML2 fusions. Compared with negative cases (n = 33), mucoepidermoid carcinomas positive for the MAML2 split (n = 62) were associated with lower patient age, a mild female predilection, a smaller tumor size, less frequent nodal metastasis, a lower clinical stage, a lower histological grade, and longer overall and disease-free survival. The MAML2 gene split emerged as an independent prognostic factor for both overall and disease-free survival in multivariate prognostic analysis. The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features. (Cancer Sci 2013; 104: 85-92) M ucoepidermoid carcinomas represent 5% of all salivary gland tumors and 20% of salivary malignancies.(1,2) A subset of these carcinomas has been associated with a recurring chromosomal translocation, t(11;19)(q21;p13), which generates a fusion protein composed of the N-terminal of cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1), also called MECT1, TORC1 or WAMP1, and the C-terminal of mastermind-like gene 2 (MAML2).(3-6) Recent data suggest that CRTC1-MAML2 induced-activation of CREB is critical for cell transformation.(5,6) CTCR1-MAML2 fusion has been detected in 40-80% of primary salivary gland mucoepidermoid carcinomas, and we and other research groups have shown that the fusion gene is associated with a distinct tumor subset with an indolent clinical course. and in Nakayama et al. (12) we reveal that CRTC3-MAML2 fusion-positive mucoepidermoid carcinoma cases have an excellent prognosis. These findings suggest that both CRTC1-MAML2 and CRTC3-MAML2 fusions may be associated with mucoepidermoid carcinoma cases with favorable clinicopathological tumor features. (13) CRTC1/3-MAML2 fusions have been detected using an RT-PCR technique, assuming that exon 1 of CRTC1/3 genes is fused to exons 2-5 of th...

show abstract

Inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia

Cited by 19 publications

References 8 publications

Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance

Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance

Covert preleukemia driven by MLL gene fusion

Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma

Contact Info

Product

Resources

About