Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Itzykson, Raphaël; Duployez, Nicolas; Fasan, Annette; Decool, Gauthier; Marceau-Renaut, Alice; Meggendorfer, Manja; Jourdan, Éric; Petit, Arnaud; Lapillonne, Hélène; Micol, Jean-Baptiste; Cornillet‐Lefèbvre, Pascale; Ifrah, Norbert; Leverger, Guy; Dombret, Hervé; Boissel, Nicolas; Haferlach, Torsten; Preudhomme, Claude

doi:10.1182/blood-2018-03-837781

Cited by 57 publications

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“…Our findings suggest that the mutatome of CBF leukemia is genetically complex with the co-existence of distinct subclones in more than half of the patients. In regards to recently published data on the prognostic impact of clonal interference in CBF leukemia [34], parallel evolution of more than one mutation in the signaling genes KIT, RAS, FLT3, JAK1/2, CBL, or PTPN11 in a single patient (assuming that these mutations arise in independent subclones) did not affect overall or RFS in our CBF leukemia cohort ( Supplementary Figs. S5 and S6).…”

Section: Discussionmentioning

confidence: 84%

The clinical mutatome of core binding factor leukemia

et al. 2020

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The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia. Supplementary informationThe online version of this article (https://

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Section: Discussionmentioning

confidence: 84%

The clinical mutatome of core binding factor leukemia

et al. 2020

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“…Mutations of KIT, FLT3 and RAS have been commonly reported in CBF AML 32,[40][41][42] . A recently published study described multiple signalling clones of KIT, FLT3 and RAS variants during clonal progression 43 , which negatively affected event-free survival (EFS), while the presence of a single signalling clone showed no such relevance. iii) Post-remission high-dose Ara-C might still exert its role on residual KITmut clones.…”

Section: (Ii)mentioning

confidence: 99%

Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Wang

Zhang

Hua

et al. 2020

Sci Rep

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Repeated cycles of post-remission high-dose cytarabine (Ara-C) have been suggested to improve survival in core binding factor (CBF) acute myeloid leukaemia (AML). High-dose Ara-C used for induction regimens has also been reported to be associated with increased treatment-related mortality (TRM). Few data are available about intermediate-dose Ara-C serving as induction therapy. The aim of our study was to compare the tolerance and outcomes of standard-and intermediate-dose levels of Ara-C as induction in CBF AML and to analyse the clinical heterogeneity of the two AML entities under these induction settings. We retrospectively investigated the outcomes in adults with CBF AML induced with regimens based on standard-dose Ara-C at 100 to 200 mg/m 2 or intermediate-dose Ara-C at 1,000 mg/ m 2 . In total, 152 patients with t(8; 21) and 54 patients with inv(16) AML were administered an induction regimen containing anthracyclines plus either standard-or intermediate-dose Ara-C. After a single course of induction, the complete remission (CR) rate in the inv(16) cohort was 52/52 (100%), higher than the 127/147 (86.4%) in the t(8; 21) cohort (P = 0.005). Intermediate-dose Ara-C (HR = 9.931 [2.135-46.188], P = 0.003) and negative KITmut (HR = 0.304 [0.106-0.874], P = 0.027) independently produced an increased CR rate in the t(8; 21) cohort. Positive CD19 expression (HR = 0.133 [0.045-0.387], P = 0.000) and sex (male) (HR = 0.238 [0.085-0.667], P = 0.006) were associated with superior leukaemia-free survival (LFS) in the t(8; 21) cohort independently of KITmut status or the induction regimen. We conclude that intermediate-dose Ara-C is superior to standard-dose Ara-C for induction of remission in t(8; 21) AML, and CD19 status and sex independently confer prognostic significance for LFS. The KITmut status alone does not have an independent effect on survival in t(8; 21) AML. More intensive induction therapy is unnecessary in inv(16) AML.Acute myeloid leukaemia (AML) with t(8; 21)(q22; q22) and AML with inv(16)(p13.1q22)/t(16; 16)(p13.1; q22) are together referred to as core binding factor (CBF) AML 1-4 , which constitutes approximately 5-8% of all de novo AML cases 5-7 . Both have been recognized as distinct diseases by the World Health Organization classification of myeloid neoplasms and acute leukaemia 8 .Overall, CBF AML has a relatively favourable clinical outcome compared to other cytogenetic subtypes. Repeated cycles of high-dose cytarabine (Ara-C) for intensification during post-remission treatment can improve survival outcomes 9-12 . However, there is considerable clinicopathological heterogeneity within this AML subset, as demonstrated by the relapse incidence reaching up to 40% and the overall survival (OS) rate of 40-60% 13-17 .Ara-C at a daily dose of 100 to 200 mg/m 2 for 7 days as induction therapy is the most widely applied strategy in most centres. Several clinical trials evaluating high-dose Ara-C as induction therapy in AML have been conducted, with results differing and the majority reporting increased treat...

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“…However, additional chromosome changes and/or gene mutations, such as + 22, + 8, deletion of 7q, and the CBL, FLT3, KIT gene mutations, are frequently found in AML with inv (16). These additional changes/mutations may influence the OS positively or negatively [6,7]. For example, gain of an additional chromosome 22 in AML with inv(16) may predict an improved outcome [6,8], whereas KIT mutations appear to have an increased risk of relapse and shorter survival in adult patients [6,9].…”

Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia with inv(16)(p13.1q22) and deletion of the 5’MYH11/3’CBFB gene fusion: a report of two cases and literature review

2020

Mol Cytogenet

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Background: Abnormalities of chromosome 16 are found in about 5-8% of acute myeloid leukemia (AML). The AML with inv(16)(p13.1q22) or t (16;16)(p13.1;q22) is associated with a high rate of complete remission (CR) and favorable overall survival (OS) when treated with high-dose Cytarabine. At the inversion breakpoints, deletion of 3'CBFB has been reported, but most of them were studied by chromosome and fluorescence in situ hybridization (FISH) analyses. The genomic characteristics of such deletions remain largely undefined, hindering further understanding of the clinical significance of the deletions. Case presentation: We report here two AML cases with inv(16) and deletion of the 5'MYH11/3'CBFB gene fusion, which were characterized by chromosome, FISH, and single nucleotide polymorphism (SNP) microarray analyses. Both cases have achieved CR for more than three years. Conclusions: Deletion of 3'CBFB in AML with inv(16) is also accompanied with deletion of 5'MYH11 in all the cases studied by SNP microarray, suggesting that 3'CBFB and 5'MYH11 were most likely deleted together as a fusion product of inv(16) instead of occurring separately. In concert with the findings of other published studies of similar patients, our study suggests that deletion of 5'MYH11/3'CBFB in AML with inv(16) may not have negative impact on the prognosis of the disease.

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Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Cited by 57 publications

References 50 publications

The clinical mutatome of core binding factor leukemia

The clinical mutatome of core binding factor leukemia

Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Acute myeloid leukemia with inv(16)(p13.1q22) and deletion of the 5’MYH11/3’CBFB gene fusion: a report of two cases and literature review

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