Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
30
03
2023
accepted:
08
08
2023
revised:
27
07
2023
medline:
2
10
2023
pubmed:
27
8
2023
entrez:
26
8
2023
Statut:
ppublish
Résumé
Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.
Identifiants
pubmed: 37634012
doi: 10.1038/s41375-023-02003-x
pii: 10.1038/s41375-023-02003-x
pmc: PMC10539177
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2082-2093Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL135795
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385–95.
pubmed: 17726160
doi: 10.1182/blood-2007-03-082404
Hussain FT, Nguyen EP, Raza S, Knudson R, Pardanani A, Hanson CA, et al. Sole abnormalities of chromosome 7 in myeloid malignancies: spectrum, histopathologic correlates, and prognostic implications. Am J Hematol. 2012;87:684–6.
pubmed: 22565657
doi: 10.1002/ajh.23230
McNerney ME, Godley LA, Le Beau MM. Therapy-related myeloid neoplasms: when genetics and environment collide. Nat Rev Cancer. 2017;17:513–27.
pubmed: 28835720
pmcid: 5946699
doi: 10.1038/nrc.2017.60
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.
pubmed: 22740453
pmcid: 4425443
doi: 10.1182/blood-2012-03-420489
Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.
pubmed: 29146900
pmcid: 5691144
doi: 10.1038/s41467-017-01590-5
Wlodarski MW, Sahoo SS, Niemeyer CM. Monosomy 7 in pediatric myelodysplastic syndromes. Hematol Oncol Clin North Am. 2018;32:729–43.
pubmed: 30047423
doi: 10.1016/j.hoc.2018.04.007
Hosono N, Makishima H, Jerez A, Yoshida K, Przychodzen B, McMahon S, et al. Recurrent genetic defects on chromosome 7q in myeloid neoplasms. Leukemia. 2014;28:1348–51.
pubmed: 24429498
pmcid: 8694066
doi: 10.1038/leu.2014.25
Afable MG, Tiu RV, Maciejewski JP. Clonal evolution in aplastic anemia. Hematol Am Soc Hematol Educ Program. 2011;2011:90–5.
doi: 10.1182/asheducation-2011.1.90
Inaba T, Honda H, Matsui H. The enigma of monosomy 7. Blood. 2018;131:2891–8.
pubmed: 29615405
doi: 10.1182/blood-2017-12-822262
Kotini AG, Chang CJ, Boussaad I, Delrow JJ, Dolezal EK, Nagulapally AB, et al. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat Biotechnol. 2015;33:646–55.
pubmed: 25798938
pmcid: 4464949
doi: 10.1038/nbt.3178
Baeten JT, Liu W, Preddy IC, Zhou N, McNerney ME. CRISPR screening in human hematopoietic stem and progenitor cells reveals an enrichment for tumor suppressor genes within chromosome 7 commonly deleted regions. Leukemia. 2022;36:1421–5.
pubmed: 35034954
pmcid: 9064908
doi: 10.1038/s41375-021-01491-z
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.
pubmed: 20601953
doi: 10.1038/ng.621
Makishima H, Jankowska AM, Tiu RV, Szpurka H, Sugimoto Y, Hu Z, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia. 2010;24:1799–804.
pubmed: 20724984
doi: 10.1038/leu.2010.167
Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24:305–17.
pubmed: 24029230
doi: 10.1016/j.ccr.2013.08.011
Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.
pubmed: 20601954
doi: 10.1038/ng.620
Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27:1806–17.
pubmed: 34621053
pmcid: 9330547
doi: 10.1038/s41591-021-01511-6
O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet. 2017;18:613–23.
pubmed: 28649135
doi: 10.1038/nrg.2017.47
Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32:748–60.e6.
pubmed: 29232553
pmcid: 5730338
doi: 10.1016/j.ccell.2017.11.003
Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
pubmed: 23634996
doi: 10.1056/NEJMoa1301689
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.
pubmed: 27276561
pmcid: 4979995
doi: 10.1056/NEJMoa1516192
Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31.
pubmed: 30333627
pmcid: 6280667
doi: 10.1038/s41586-018-0623-z
Adema V, Palomo L, Walter W, Mallo M, Hutter S, La Framboise T, et al. Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q. EBioMedicine. 2022;80:104059.
pubmed: 35617825
pmcid: 9130225
doi: 10.1016/j.ebiom.2022.104059
Jerez A, Sugimoto Y, Makishima H, Verma A, Jankowska AM, Przychodzen B, et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood. 2012;119:6109–17.
pubmed: 22553315
pmcid: 3383019
doi: 10.1182/blood-2011-12-397620
Awada H, Durmaz A, Gurnari C, Kishtagari A, Meggendorfer M, Kerr CM, et al. Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia. Blood. 2021;138:1885–95.
pubmed: 34075412
pmcid: 8767789
doi: 10.1182/blood.2020010603
Meggendorfer M, Haferlach C, Kern W, Haferlach T. Molecular analysis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5 reveals a specific spectrum of molecular mutations with prognostic impact: a study on 123 patients and 27 genes. Haematologica. 2017;102:1502–10.
pubmed: 28642303
pmcid: 5685225
doi: 10.3324/haematol.2017.166173
Meggendorfer M, Cappelli LV, Walter W, Haferlach C, Kern W, Falini B, et al. IDH1R132, IDH2R140 and IDH2R172 in AML: different genetic landscapes correlate with outcome and may influence targeted treatment strategies. Leukemia. 2018;32:1249–53.
pubmed: 29568090
doi: 10.1038/s41375-018-0026-z
Palomo L, Meggendorfer M, Hutter S, Twardziok S, Ademà V, Fuhrmann I, et al. Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. Blood. 2020;136:1851–62.
pubmed: 32573691
pmcid: 7645608
doi: 10.1182/blood.2019004229
Kubota Y, Zawit M, Durrani J, Shen W, Bahaj WS, Kewan T, et al. Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia. Leukemia. 2022;36:2827–34.
pubmed: 36266327
doi: 10.1038/s41375-022-01729-4
McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C, et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood. 2013;121:975–83.
pubmed: 23212519
pmcid: 3567344
doi: 10.1182/blood-2012-04-426965
Sundaravel S, Kuo WL, Jeong JJ, Choudhary GS, Gordon-Mitchell S, Liu H, et al. Loss of function of DOCK4 in myelodysplastic syndromes stem cells is restored by inhibitors of DOCK4 signaling networks. Clin Cancer Res. 2019;25:5638–49.
pubmed: 31308061
pmcid: 6744990
doi: 10.1158/1078-0432.CCR-19-0924
Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature. 2019;568:511–6.
pubmed: 30971826
doi: 10.1038/s41586-019-1103-9
Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a cancer dependency map. Cell. 2017;170:564–76.e16.
pubmed: 28753430
pmcid: 5667678
doi: 10.1016/j.cell.2017.06.010
Crisà E, Kulasekararaj AG, Adema V, Such E, Schanz J, Haase D, et al. Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7. Leukemia. 2020;34:2441–50.
pubmed: 32066866
doi: 10.1038/s41375-020-0728-x
Gur HD, Wang SA, Tang Z, Hu S, Li S, Medeiros LJ, et al. Clinical significance of isolated del(7p) in myeloid neoplasms. Leuk Res. 2017;55:18–22.
pubmed: 28119224
doi: 10.1016/j.leukres.2017.01.016
Schneider RK, Delwel R. Puzzling pieces of chromosome 7 loss or deletion. Blood. 2018;131:2871–2.
pubmed: 29954818
doi: 10.1182/blood-2018-04-844746
Wong JC, Weinfurtner KM, Alzamora MEP, Kogan SC, Burgess MR, Zhang Y, et al. Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis. eLife. 2015;4:e07839.
pubmed: 26193121
pmcid: 4569895
doi: 10.7554/eLife.07839
Ramdzan ZM, Nepveu A. CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers. Nat Rev Cancer. 2014;14:673–82.
pubmed: 25190083
doi: 10.1038/nrc3805
Singh H, Lane AA, Correll M, Przychodzen B, Sykes DB, Stone RM. et al. Putative RNA-splicing gene LUC7L2 on 7q34 represents a candidate gene in pathogenesis of myeloid malignancies. Blood Cancer J. 2013;3:e117
pubmed: 23708642
pmcid: 3674458
doi: 10.1038/bcj.2013.16
Voso MT, Falconi G, Fabiani E. What’s new in the pathogenesis and treatment of therapy-related myeloid neoplasms. Blood. 2021;138:749–57.
pubmed: 33876223
doi: 10.1182/blood.2021010764
Goyal S, Tisdale J, Schmidt M, Kanter J, Jaroscak J, Whitney D, et al. Acute myeloid leukemia case after gene therapy for sickle cell disease. N Engl J Med. 2022;386:138–47.
pubmed: 34898140
doi: 10.1056/NEJMoa2109167
Negoro E, Nagata Y, Clemente MJ, Hosono N, Shen W, Nazha A, et al. Origins of myelodysplastic syndromes after aplastic anemia. Blood. 2017;130:1953–7.
pubmed: 28893734
pmcid: 5659066
doi: 10.1182/blood-2017-02-767731
Zhao R, Yeung SC, Chen J, Iwakuma T, Su CH, Chen B, et al. Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers. J Clin Invest. 2011;121:851–65.
pubmed: 21317535
pmcid: 3049400
doi: 10.1172/JCI44111
Herceg Z, Hulla W, Gell D, Cuenin C, Lleonart M, Jackson S, et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet. 2001;29:206–11.
pubmed: 11544477
doi: 10.1038/ng725
Nakagawa T, Nakayama K, Nakayama KI. Knockout mouse models provide insight into the biological functions of CRL1 components. Adv Exp Med Biol. 2020;1217:147–71.
pubmed: 31898227
doi: 10.1007/978-981-15-1025-0_10
Luong MX, van der Meijden CM, Xing D, Hesselton R, Monuki ES, Jones SN, et al. Genetic ablation of the CDP/Cux protein C terminus results in hair cycle defects and reduced male fertility. Mol Cell Biol. 2002;22:1424–37.
pubmed: 11839809
pmcid: 134686
doi: 10.1128/MCB.22.5.1424-1437.2002
O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol. 2001;21:4330–6.
pubmed: 11390661
pmcid: 87093
doi: 10.1128/MCB.21.13.4330-4336.2001
Aly M, Ramdzan ZM, Nagata Y, Balasubramanian SK, Hosono N, Makishima H, et al. Distinct clinical and biological implications of. Blood Adv. 2019;3:2164–78.
pubmed: 31320321
pmcid: 6650742
doi: 10.1182/bloodadvances.2018028423
Meng Y, Wang L, Chen D, Chang Y, Zhang M, Xu JJ, et al. LAPTM4B: an oncogene in various solid tumors and its functions. Oncogene. 2016;35:6359–65.
pubmed: 27212036
pmcid: 5161753
doi: 10.1038/onc.2016.189
Lang S, Busch H, Boerries M, Brummer T, Timme S, Lassmann S, et al. Specific role of RhoC in tumor invasion and metastasis. Oncotarget. 2017;8:87364–78.
pubmed: 29152087
pmcid: 5675639
doi: 10.18632/oncotarget.20957