Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia

Sydney Fobare, Jessica Kohlschmidt, Hatice Gulcin Ozer, Krzysztof Mrózek, Deedra Nicolet, Alice S Mims, Ramiro Garzon, James S Blachly, Shelley Orwick, Andrew J Carroll, Richard M Stone, Eunice S Wang, Jonathan E Kolitz, Bayard L Powell, Christopher C Oakes, Ann-Kathrin Eisfeld, Erin Hertlein, John C Byrd, Sydney Fobare, Jessica Kohlschmidt, Hatice Gulcin Ozer, Krzysztof Mrózek, Deedra Nicolet, Alice S Mims, Ramiro Garzon, James S Blachly, Shelley Orwick, Andrew J Carroll, Richard M Stone, Eunice S Wang, Jonathan E Kolitz, Bayard L Powell, Christopher C Oakes, Ann-Kathrin Eisfeld, Erin Hertlein, John C Byrd

Abstract

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Oncoprint of mutations co-occurring with PTPN11 mutations and PTPN11 mutation VAFs in patients with AML. Each column represents an individual patient. The top row represents PTPN11 VAFs, ranging from 0.05 (blue) to 0.54 (yellow). Each subsequent row represents a gene. Green squares indicate the presence of a mutation, insertion, or deletion; gray squares represent no alteration detected; and white squares represent unavailable gene alteration status.
Figure 2.
Figure 2.
Lollipop plot depicting the location of PTPN11 mutations. aa, amino acid.
Figure 3.
Figure 3.
Outcomes of patients with mutations in the N-SH2 domain of the PTPN11 gene vs mutations in the PTP domain. (A) DFS based on the presence of an N-SH2 domain (blue line) or PTP domain (red line) PTPN11 mutation. (B) OS for patients with an N-SH2 domain (blue line) or PTP domain (red line) PTPN11 mutation. (C) EFS based on the presence of an N-SH2 domain (blue line) or PTP domain (red line) PTPN11 mutation.
Figure 4.
Figure 4.
OS of younger (age <60 years) patients. (A) OS in younger patients with NPM1mut/PTPN11wt (blue line) and NPM1mut/PTPN11mut (red line). (B) OS for younger patients based on the presence of NPM1wt/PTPN11wt (blue line) and NPM1wt/PTPN11mut (red line).

References

    1. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441.
    1. Döhner H, Estey EH, Amadori S, et al. ; European LeukemiaNet . Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
    1. Qu CK, Shi ZQ, Shen R, Tsai FY, Orkin SH, Feng G-S. A deletion mutation in the SH2-N domain of Shp-2 severely suppresses hematopoietic cell development. Mol Cell Biol. 1997;17(9):5499-5507.
    1. Salmond RJ, Alexander DR. SHP2 forecast for the immune system: fog gradually clearing. Trends Immunol. 2006;27(3):154-160.
    1. Pei D, Wang J, Walsh CT. Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1. Proc Natl Acad Sci USA. 1996;93(3):1141-1145.
    1. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92(4):441-450.
    1. Barford D, Neel BG. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure. 1998;6(3):249-254.
    1. Fragale A, Tartaglia M, Wu J, Gelb BD. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004;23(3):267-277.
    1. Tartaglia M, Mehler EL, Goldberg R, et al. . Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome [published corrections appear in Nat Genet. 2001;29(4):491 and Nat Genet. 2002;30(1):123]. Nat Genet. 2001;29(4):465-468.
    1. Digilio MC, Conti E, Sarkozy A, et al. . Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71(2):389-394.
    1. Tartaglia M, Niemeyer CM, Fragale A, et al. . Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34(2):148-150.
    1. Chen L, Chen W, Mysliwski M, et al. . Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition. Leukemia. 2015;29(6):1290-1300.
    1. Tsai C-H, Hou HA, Tang JL, et al. . Genetic alterations and their clinical implications in older patients with acute myeloid leukemia. Leukemia. 2016;30(7):1485-1492.
    1. Ley TJ, Miller C, Ding L, et al. ; Cancer Genome Atlas Research Network . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
    1. Ok CY, Patel KP, Garcia-Manero G, et al. . Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases. Leuk Res. 2015;39(3):348-354.
    1. DiNardo CD, Stein EM, de Botton S, et al. . Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
    1. Amatangelo MD, Quek L, Shih A, et al. . Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732-741.
    1. Chyla B, Daver N, Doyle K, et al. . Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018;93(8):E202-E205.
    1. Zhang H, Nakauchi Y, Köhnke T, et al. . Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia. Nat Cancer. 2020;1(8):826-839.
    1. Cremer A, Ellegast JM, Alexe G, et al. . Resistance mechanisms to SYK inhibition in acute myeloid leukemia. Cancer Discov. 2020;10(2):214-231.
    1. Eisfeld A-K, Mrózek K, Kohlschmidt J, et al. . The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia. 2017;31(10):2211-2218.
    1. Mrózek K, Carroll AJ, Maharry K, et al. . Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: the Cancer and Leukemia Group B experience. Int J Oncol. 2008;33(2):239-244.
    1. Whitman SP, Archer KJ, Feng L, et al. . Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233-7239.
    1. Marcucci G, Maharry K, Radmacher MD, et al. . Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol. 2008;26(31):5078-5087.
    1. Döhner H, Estey E, Grimwade D, et al. . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
    1. Vittinghoff E, Glidden D, Shiboski SC, McCulloch C. Regression Methods in Biostatistics: Linear, Logistic, Survival and Repeated Measure Models. New York, NY: Springer; 2005
    1. Alfayez M, Issa GC, Patel KP, et al. . The clinical impact of PTPN11 mutations in adults with acute myeloid leukemia. Leukemia. 2021;35(3):691-700.
    1. Gao J, Aksoy BA, Dogrusoz U, et al. . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
    1. Cerami E, Gao J, Dogrusoz U, et al. . The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404.
    1. Bentires-Alj M, Paez JG, David FS, et al. . Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004;64(24):8816-8820.
    1. Byrd JC, Mrózek K, Dodge RK, et al. ; Cancer and Leukemia Group B (CALGB 8461) . Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100(13):4325-4336.
    1. Grimwade D, Mrózek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol Oncol Clin North Am. 2011;25(6):1135-1161, vii.
    1. Gröschel S, Sanders MA, Hoogenboezem R, et al. . Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. Blood. 2015;125(1):133-139.
    1. Mrózek K, Eisfeld A-K, Kohlschmidt J, et al. . Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically. Leukemia. 2019;33(7):1620-1634.
    1. Swoboda DM, Ali NA, Chan O, et al. . PTPN11 mutations are associated with poor outcomes across myeloid malignancies. Leukemia. 2021;35(1):286-288.
    1. Kaner JD, Mencia-Trinchant N, Schaap A, et al. . Acute myeloid leukemia (AML) with somatic mutations in PTPN11 is associated with treatment resistance and poor overall survival [abstract]. Blood. 2018;132(suppl 1). Abstract 2760.
    1. Hou HA, Chou WC, Lin LI, et al. . Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. Leukemia. 2008;22(5):1075-1078.
    1. Choe S, Wang H, DiNardo CD, et al. . Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 2020;4(9):1894-1905.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren