Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways

Gröschel, Stefan; Sanders, Mathijs A.; Hoogenboezem, Remco M.; Zeilemaker, Annelieke; Havermans, Marije; Erpelinck, Claudia; Bindels, Eric; Beverloo, H. Berna; Döhner, Hartmut; Löwenberg, Bob; Döhner, Konstanze; Delwel, Ruud; Valk, Peter J.M.

doi:10.1182/blood-2014-07-591461

Cited by 79 publications

(80 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Two patients harbored the same SMC1A variant R96H, previously reported in AML. 33 We found a hotspot in SMC3 because 3 of 5 mutations involved the codon R661 in the hinge domain of the protein.…”

Section: Gene Mutationsmentioning

confidence: 99%

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

192

186

View full text Add to dashboard Cite

Key Points• Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML, but not inv (16 . Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.

show abstract

Section: Gene Mutationsmentioning

confidence: 99%

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

192

186

View full text Add to dashboard Cite

show abstract

“…25 A recent study demonstrated that mutations activating RAS/receptor tyrosine kinase pathway are coupled with EVI1 overexpression in 98% of inv(3)/t(3;3) cases and contribute to leukemic transformation. 26 Although studies have shown that 3q26.2 abnormalities in AML are associated with an unfavorable prognosis, the role of 3q26.2 in CML is largely unknown. Only occasional single-case reports and small case series composed of few cases are available in the literature.…”

Section: Introductionmentioning

confidence: 99%

Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors

Wang¹,

Cortes

Lin³

et al. 2015

Blood

View full text Add to dashboard Cite

• The emergence of 3q26.2 rearrangements in CML is associated with resistance to TKI treatment and poor prognosis.• 3q26.2 rearrangements play a predominant role in determining prognosis, irrelevant to the presence or absence of other additional chromosomal abnormalities in CML.Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non-3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort.

show abstract

“…They further showed that although alterations of KRAS, NF1, and RUNX1 were more frequent in AML than MDS, the differences were not statistically significant. 16 By using next-generation sequencing, including whole-transcriptome and whole-exome sequencing, Gröschel and associates 21 have showed that mutations in genes activating RAS/ receptor tyrosine kinase occur in 98% of myeloid neoplasms with inv(3)/t(3;3), and these mutations were mainly present in the dominant ectopic viral integration site 1 (EVI1)-rearranged clone. These authors further demonstrated the strong homogeneity between inv(3)/t(3;3)-harboring AML and MDS based on gene expression profiling and the pattern of cooperating genetic lesions using cluster and principal component analyses.…”

mentioning

confidence: 99%

The New Clinicopathologic and Molecular Findings in Myeloid Neoplasms With inv(3)(q21q26)/t(3;3)(q21;q26.2)

Wang

Rashidi

2016

Archives of Pathology &Amp; Laboratory Medicine

View full text Add to dashboard Cite

Context.-Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast crisis of myeloproliferative neoplasms. Recent advances on myeloid neoplasms with inv(3)/t(3;3) with regard to clinicopathologic features and novel molecular or genomic findings warrant a comprehensive review on this topic.Objective.-To review the clinicopathologic features and molecular as well as genomic alterations in myeloid neoplasms with inv(3)/t(3;3).Data Sources.-The data came from published articles in English-language literature.Conclusions.-At the clinicopathologic front, recent studies on MDS with inv(3)/t(3;3) have highlighted their overlapping clinicopathologic features with and similar overall survival to that of inv(3)/t(3;3)-harboring AML regardless of the percentage of myeloid blasts. On the molecular front, AML and MDS with inv(3)/t(3;3) exhibit gene mutations, which affect the RAS/receptor tyrosine kinase pathway. Furthermore, functional genomic studies using genomic editing and genome engineering have shown that the reallocation of the GATA2 distal hematopoietic enhancer to the proximity of the promoter of ectopic virus integration site 1 (EVI1) without the formation of a new oncogenic fusion transcript is the molecular mechanism underlying these inv(3)/t(3;3) myeloid neoplasms. Although the AML and MDS with inv(3)/t(3;3) are listed as a separate category of myeloid malignancies in the 2008 World Health Organization classification, the overlapping clinicopathologic features, similar overall survival, and identical patterns at the molecular and genomic levels between AML and MDS patients with inv(3)/t(3;3) may collectively favor a unification of AML and MDS with inv(3)/t(3;3) as AML or myeloid neoplasms with inv(3)/t(3;3) regardless of the blast count.(Arch Pathol Lab Med. 2016;140:1404-1410; doi: 10.5858/arpa.2016-0059-RA) B efore we review the recent advances of myeloid neoplasms with inv(3)(q21q26)/t(3;3)(q21;q26.2) [referred to as inv(3)/t(3;3) hereafter], the clinicopathologic features of inv(3)/t(3;3) are worth being mentioned here. The structural changes involving the long arm of chromosome 3 at bands 3q21 and 3q26.2 in the forms of inversion and translocation-namely, paracentric inversion [inv(3)(q21q26.2), referred to as inv (3) hereafter] and homologous translocations [t(3;3)(q21;q26.2), referred to as t(3;3) hereafter]-in myeloid neoplasms have long been recognized. [1][2][3][4][5] Together inv(3), t(3;3), and sometimes insertions (ins) [ins(3;3)(q26;q21q26)] or duplications (dup) [dup(3)(q21-q26)] of these chromosomal regions are collectively termed as a 3q21q26 syndrome.5 Myeloid neoplasms with 3q21q26 anomalies are not only seen in acute myeloid leukemias (AMLs), 6,7 but also in myelodysplastic syndromes (MDS) 5; blast crisis of myeloproliferative neoplasm (MPN), such as chronic myelogenous leukemia 8 or leukemic transformation of essen...

show abstract

Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways

Cited by 79 publications

References 52 publications

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors

The New Clinicopathologic and Molecular Findings in Myeloid Neoplasms With inv(3)(q21q26)/t(3;3)(q21;q26.2)

Contact Info

Product

Resources

About