Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 12;7(17):5000-5013.
doi: 10.1182/bloodadvances.2023009675.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia

Affiliations

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia

Joseph G W McCarter et al. Blood Adv. .

Abstract

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: M.E.A. served as a consultant for Janssen Global Services, Bristol Myers Squibb (BMS), AstraZeneca, and Roche, and has received honoraria from Biocartis, Invivoscribe, physician educational resources, PeerView Institute for Medical Education, clinical care options, and RMEI Medical Education. A.J.S. reports his spouse is an employee of BMS. B.J.B. served on the advisory board for Oncovalent and BMS. S.F.C. is a consultant for and holds an equity interest in Imago BioSciences, none of which is directly related to the content of this paper. J.L.G. received consulting fees from GLG. M.B.G. receives research support from Actinium, Amgen, and Sanofi, and has served in an advisory role for Sanofi, Novartis, and Allogene. R.K.R. has received consulting fees from Incyte Corporation, Celgene/BMS, Blueprint, AbbVie, CTI, Stemline, Galecto, Pharmaessentia, Constellation/MorphoSys, Sierra Oncology/GlaxoSmithKline, Sumitomo Dainippon, Kartos, Servier, Zentalis, Karyopharm, and research funding from Constellation Pharmaceuticals, Ryvu, Zentalis, and Stemline Therapeutics. O.I.A.-W. served as a consultant for H3 Biomedicine, Foundation Medicine Inc, Merck, Prelude Therapeutics, and Janssen; is on the scientific advisory board of Envisagenics Inc, AIChemy, Harmonic Discovery Inc, and Pfizer Boulder; and has received prior research funding from H3 Biomedicine, Nurix Therapeutics, Minovia Therapeutics, and Loxo Oncology, unrelated to the current manuscript. A.D.G. received research funding from Celularity, ADC Therapeutics, Aprea, AROG, Pfizer, Prelude, and Trillium; received research funding from and served as a consultant for Aptose and Daiichi Sankyo; served as a consultant and member of the advisory committees for Astellas, Celgene, and Genentech; received research funding from, served as a consultant for, and was a member of the advisory committees for AbbVie; and received honoraria from Dava Oncology. M.S.T. received research funding from AbbVie, Orsenix, BioSight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; is on the advisory boards of AbbVie, Daiichi Sankyo, Orsenix, KAHR, Jazz Pharmaceuticals, Roche, BioSight, Novartis, Innate Pharmaceuticals, Kura, Syros Pharmaceuticals, and Ipsen Biopharmaceuticals; received royalties from UpToDate; and is on the DSMB of HOVON protocol Ho156 and adjudication committee of Foghorn protocol FHD-286. R.L.L. is on the supervisory board of Qiagen and is a scientific adviser to Imago, Mission Bio, Syndax, Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics, and Isoplexis for which he receives equity support; receives research support from Ajax and AbbVie; has consulted for Incyte, Janssen, MorphoSys, and Novartis; and received honoraria from AstraZeneca and Kura for invited lectures and from Gilead for grant reviews. E.P. is a founder and equity holder, and holds a fiduciary role in Isabl Inc. M.R. is on the scientific advisory board in Auron Pharmaceutical for which he received equity support; receives research funding from Celularity, Roche-Genentech, Beat AML, and NGM; and receives travel funds from BD Biosciences. W.X. received research support from Stemline Therapeutics. The remaining authors declare no competing financial interests.

The current affiliation for Z.S.S.-M. is Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY.

The current affiliation for J.C. is Weill Cornell Medicine, New York City, NY.

The current affiliation for B.J.B. is City of Hope National Medical Center, Duarte, CA.

The current affiliation for M.S.T. is Northwestern University, Chicago, IL.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Genomic profiling predicts the AML ontogeny. (A) Oncoplot of AML subtypes (de novo AML, t-AML, MR-Hx, and MR-CG). NGS panels are indicated as platforms (RDTS, RDTB, and IMPACT-heme). Genes not covered by RDTS are indicated in gray. The ELN2017 and ELN2022 risk groups are listed. EVI1 indicates EVI1 rearrangements. MLL indicates MLL rearrangements. (B) Bar plots of genomic aberrations for each AML subtype. Proportions are shown. The MR/RUNX1 genes are bolded. (C) Association between individual gene mutations and AML ontogeny. Odds ratio was depicted on a log10 scale. The comparison is between MR-Hx and de novo AML.
Figure 2.
Figure 2.
Distribution of AML ontogeny subtypes in each genomic class. The width of each bar indicates the number of patients. MR indicates patients with AML with MR gene mutations (including ASXL1, BCOR, EZH2, STAG2, SF3B1, SRSF2, ZRSR2, and U2AF1, but no RUNX1 mutations). MR-RUNX1 indicates patients with AML with both MR gene and RUNX1 gene mutations. RUNX1 indicates patients with AML with RUNX1 but no MR gene mutations. MR/RUNX1 indicates patients with AML with MR and/or RUNX1 gene mutations. NOS indicates patients with AML with mutations detected but cannot be assigned to a well-defined entity. NEG indicates patients with AML with no mutations or rearrangements detected.
Figure 3.
Figure 3.
Both AML ontogeny and ELN risk have independent prognostic values. (A) Kaplan-Meier curves of OS divided by AML ontogeny subtypes. (B) Kaplan-Meier curves of OS divided by genomic classes. Both patients with t(6;9) underwent allo-HSCT. (C) AML ontogeny–related risk was evaluated using multivariable Cox-regression models adjusted for age (modeled by cubic spline), initial treatment at diagnosis, allogenic transplant (modeled as a time-dependent variable), and genomic classes. 7 + 3, daunorubicin + cytarabine, including CPX-351. HMA, hypomethylating agents; low DAC, low-dose cytarabine.
Figure 4.
Figure 4.
AML ontogeny determines the outcome of AML with MR/RUNX1 gene mutations. (A) Kaplan-Meier curves of OS of AML with MR/RUNX1 gene mutations divided by ontogeny. (B) AML ontogeny–related risk was evaluated in multivariable Cox-regression models adjusting for age (modeled by cubic spline), allogenic transplant (modeled as time-dependent variable), NRAS/KRAS mutations, and CG risks in patients with AML with MR/RUNX1 mutations uniformly treated with 7+3 induction therapy. (C) Kaplan-Meier curves of patients with AML were divided into ELN2022 risk groups. De novo AML with MR/RUNX1 gene mutations separated from the ELN2022 adverse group show an outcome falling in between the favorable and intermediate-risk groups.

References

    1. Pollyea DA, Bixby D, Perl A, et al. NCCN guidelines insights: acute myeloid leukemia, version 2.2021. J Natl Compr Canc Netw. 2021;19(1):16–27. - PubMed
    1. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345–1377. - PubMed
    1. Bennett JM, Catovsky D, Daniel M-T, et al. Proposals for the classification of the Acute Leukaemias French-American-British (FAB) Co-operative Group. Br J Haematol. 1976;33(4):451–458. - PubMed
    1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. - PubMed
    1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–951. - PubMed

Publication types