Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
   PubMed Web of Science ®Google Scholar
• Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006 05–0100:00:00;107(9):3481–3485.
   PubMed Web of Science ®Google Scholar
• Howlader NNA, Krapcho M, Garshell J, et al., editors. SEER cancer statistics review, 1975–2012. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2012/. based on November 2014 SEER data submission, posted to the SEER web site, April 2015.
   Google Scholar
• Dennis M, Culligan D, Karamitros D, et al. Lenalidomide monotherapy and in combination with cytarabine, daunorubicin and etoposide for high-risk myelodysplasia and acute myeloid leukaemia with chromosome 5 abnormalities. Leuk Res Rep. 2013;2(2):70–74. PubMed PMID: 24371786; PubMed Central PMCID: PMCPmc3850387. eng
   PubMedGoogle Scholar
• Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–2692. PubMed PMID: 30024784
   PubMed Web of Science ®Google Scholar
• Decker RH, Dai Y, Grant S. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ. 2001 Jul;8(7):715–724. PubMed PMID: 11464216; eng.
   PubMed Web of Science ®Google Scholar
• Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379–389. PubMed PMID: 30555165; PubMed Central PMCID: PMCPMC6365492. eng.
   PubMed Web of Science ®Google Scholar
• Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014 Mar;164(6):811–821. PubMed PMID: 24328678; eng.
   PubMed Web of Science ®Google Scholar
• Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–464. PubMed PMID: 28644114
   PubMed Web of Science ®Google Scholar
• Xu Y, Sun J, Sheard MA, et al. Lenalidomide overcomes suppression of human natural killer cell anti-tumor functions by neuroblastoma microenvironment-associated IL-6 and TGFbeta1. Cancer Immunol Immunother. 2013 Oct;62(10):1637–1648. PubMed PMID: 23982484; PubMed Central PMCID: PMCPmc3907789. eng.
   PubMed Web of Science ®Google Scholar
• Levis MJ, Perl AE, Martinelli G, et al. Effect of gilteritinib on survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) AML who have common AML co-mutations or a high FLT3-ITD allelic ratio [abstract]. J Clin Oncol. 2019;37:7000.
   Web of Science ®Google Scholar
• Wu L, Li X, Xu F, et al. Low RPS14 expression in MDS without 5q - aberration confers higher apoptosis rate of nucleated erythrocytes and predicts prolonged survival and possible response to lenalidomide in lower risk non-5q- patients. Eur J Haematol. 2013 Jun;90(6):486–493. PubMed PMID: 23506134; eng.
   PubMed Web of Science ®Google Scholar
• 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. PubMed PMID: 29860938
   PubMed Web of Science ®Google Scholar
• Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study [abstract]. Blood. 2018;132(Suppl 1):561.
   Web of Science ®Google Scholar
• Attar EC, Amrein PC, Fraser JW, et al. Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Leuk Res. 2013 Sep;37(9):1016–1020. PubMed PMID: 23773898; PubMed Central PMCID: PMCPmc3969839. eng.
   PubMed Web of Science ®Google Scholar
• Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–731.
   PubMed Web of Science ®Google Scholar
• Platzbecker U, Braulke F, Kundgen A, et al. Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk myelodysplastic syndromes or acute myeloid leukemia: a phase I study. Leukemia. 2013 Jun;27(6):1403–1407. PubMed PMID: 23354011; PubMed Central PMCID: PMCPmc3677141. eng.
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
   PubMed Web of Science ®Google Scholar
• Wei AH, Strickland SA Jr., Hou JZ, et al. venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019 May 20;37(15):1277–1284. PubMed PMID: 30892988; PubMed Central PMCID: PMCPMC6524989. eng.
   PubMed Web of Science ®Google Scholar
• Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140(15):3079–3093.
   PubMed Web of Science ®Google Scholar
• Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014 June 30;15(6):122.
   PubMed Web of Science ®Google Scholar
• Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy [review article]. Nat Rev Cancer. 2017 Jan 27 online;17:93. https://www.nature.com/articles/nrc.2016.138#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Aleem E, Arceci RJ. Targeting cell cycle regulators in hematologic malignancies [review]. Front Cell Dev Biol. 2015 April 09;3(16). English. DOI:10.3389/fcell.2015.00016.
   PubMed Web of Science ®Google Scholar
• Peng J, Zhu Y, Milton JT, et al. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 1998 March 1;12(5):755–762.
   PubMed Web of Science ®Google Scholar
• Zhu Y, Pe’ery T, Peng J, et al. Transcription elongation factor P-TEFb is required for HIV-1 Tat transactivation in vitro. Genes Dev. 1997 October 15;11(20):2622–2632.
   PubMed Web of Science ®Google Scholar
• Marshall NF, Peng J, Xie Z, et al. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain Kinase. J Biol Chem. 1996 October 25;271(43):27176–27183.
   PubMed Web of Science ®Google Scholar
• Hnisz D, Abraham Brian J, Lee Tong I, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013 Nov 07;155(4):934–947.
   PubMed Web of Science ®Google Scholar
• Kozopas KM, Yang T, Buchan HL, et al. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Nat Acad Sci. 1993;90(8):3516–3520.
   PubMed Web of Science ®Google Scholar
• Juin P, Geneste O, Gautier F, et al. Decoding and unlocking the BCL-2 dependency of cancer cells [review article]. Nat Rev Cancer. 2013 June 20 online;13:455.
   PubMed Web of Science ®Google Scholar
• De Blasio A, Vento R, Di Fiore R. Mcl-1 targeting could be an intriguing perspective to cure cancer. J Cell Physiol. 2018 Nov;233(11):8482–8498. PubMed PMID: 29797573; eng.
   PubMed Web of Science ®Google Scholar
• Bose P, Grant S. Mcl-1 as a therapeutic target in acute myelogenous leukemia (AML). Leuk Res Rep. 2013 Jan 1;2(1):12–14. PubMed PMID: 23977453; PubMed Central PMCID: PMCPMC3747011. eng.
   PubMedGoogle Scholar
• Reynolds JE, Yang T, Qian L, et al. Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 1994;54(24):6348–6352.
   PubMed Web of Science ®Google Scholar
• Zhou P, Qian L, Kozopas KM, et al. Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. Blood. 1997;89(2):630–643.
   PubMed Web of Science ®Google Scholar
• Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012 January 15;26(2):120–125.
   PubMed Web of Science ®Google Scholar
• Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010 June 01;120(6):2109–2118.
   PubMed Web of Science ®Google Scholar
• Kaufmann SH, Karp JE, Svingen PA, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998;91(3):991–1000.
   PubMed Web of Science ®Google Scholar
• Niu X, Zhao J, Ma J, et al. Binding of released BIM to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22(17):4440–4451.
   PubMed Web of Science ®Google Scholar
• Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan 08 online;26:127. https://www.nature.com/articles/nbt1358#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Kaur G, Stetler-Stevenson M, Sebers S, et al. Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. JNCI. 1992;84(22):1736–1740.
   PubMedGoogle Scholar
• Carlson BA, Dubay MM, Sausville EA, et al. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996;56(13):2973–2978.
   PubMed Web of Science ®Google Scholar
• Parker BW, Kaur G, Nieves-Neira W, et al. Early Induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood. 1998;91(2):458–465.
   PubMed Web of Science ®Google Scholar
• Kitada S, Zapata JM, Andreeff M, et al. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood. 2000;96(2):393–397.
   PubMed Web of Science ®Google Scholar
• Pepper C, Thomas A, Hoy T, et al. Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia. Br J Haematol. 2001;114(1):70–77.
   PubMed Web of Science ®Google Scholar
• Gojo I, Zhang B, Fenton RG. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of MCL-1. Clin Cancer Res. 2002;8(11):3527–3538.
   PubMed Web of Science ®Google Scholar
• Karp JE, Ross DD, Yang W, et al. Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin Cancer Res. 2003;9(1):307–315.
   PubMed Web of Science ®Google Scholar
• Ma Y, Cress WD, Haura EB. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of MCL-1. Mol Cancer Ther. 2003;2(1):73–81.
   PubMed Web of Science ®Google Scholar
• Chao SH, Fujinaga K, Marion JE, et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem. 2000 Sep 15;275(37):28345–28348. PubMed PMID: 10906320; eng.
   PubMed Web of Science ®Google Scholar
• Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem. 2001 Aug 24;276(34):31793–31799. PubMed PMID: 11431468; eng.
   PubMed Web of Science ®Google Scholar
• Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol. 2001;2(10):RESEARCH0041. PubMed PMID: 11597333; PubMed Central PMCID: PMCPMC57796. eng.
   PubMed Web of Science ®Google Scholar
• Karp JE, Passaniti A, Gojo I, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-β-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res. 2005;11(23):8403–8412.
   PubMed Web of Science ®Google Scholar
• Karp JE, Smith BD, Levis MJ, et al. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous leukemia. Clin Cancer Res. 2007;13(15):4467–4473.
   PubMed Web of Science ®Google Scholar
• Karp JE, Blackford A, Smith BD, et al. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk Res. 2010 July 01;34(7):877–882.
   PubMed Web of Science ®Google Scholar
• Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172–1179.
   PubMed Web of Science ®Google Scholar
• Döhner H, Estey EH, Amadori S, et al. 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.
   PubMed Web of Science ®Google Scholar
• Zeidner JF, Foster MC, Blackford AL, et al. Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML). Leuk Res. 2018 Sep;72:92–95. PubMed PMID: 30118897; eng.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood. 2007;109(2):399–404.
   PubMed Web of Science ®Google Scholar
• Blum W, Phelps MA, Klisovic RB, et al. Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica. 2010;95(7):1098–1105.
   PubMed Web of Science ®Google Scholar
• Karp JE, Smith BD, Resar LS, et al. Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 2011;117(12):3302–3310.
   PubMed Web of Science ®Google Scholar
• Karp JE, Garrett-Mayer E, Estey EH, et al. Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Haematologica. 2012 Nov;97(11):1736–1742. PubMed PMID: 22733022; PubMed Central PMCID: PMCPmc3487449. eng.
   PubMed Web of Science ®Google Scholar
• Smith BD, Warner SL, Whatcott C, et al. An alvocidib-containing regimen is highly effective in AML patients through a mechanism dependent on MCL1 expression and function [abstract]. J Clin Oncol. 2015;33(15_suppl):7062.
   Web of Science ®Google Scholar
• Ryan JA, Brunelle JK, Letai A. Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Nat Acad Sci. 2010;107(29):12895–12900.
   PubMed Web of Science ®Google Scholar
• Montero J, Sarosiek Kristopher A, DeAngelo Joseph D, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015 Feb 26;160(5):977–989.
   PubMed Web of Science ®Google Scholar
• Montero J, Letai A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 2018 Jan;25(1):56–64. PubMed PMID: 29077093; PubMed Central PMCID: PMCPMC5729538. eng
   PubMed Web of Science ®Google Scholar
• Zeidner JF, Lin TL, Vigil CE, et al. Zella 201: a biomarker-guided phase ii study of alvocidib followed by cytarabine and mitoxantrone in MCL-1 dependent relapsed/refractory acute myeloid leukemia (AML) [abstract]. Blood. 2018;132(Suppl 1):30
   Web of Science ®Google Scholar
• Lee D, Smith B, Frattini M, et al. Zella-101: phase 1 study of alvocidib followed by 7+3 induction in newly diagnosed AML patients [abstract]. HemaSphere. 2019;3:94. PubMed PMID: 02014419-201906001-00184
   Google Scholar
• Bogenberger J, Whatcott C, Hansen N, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017 Dec 5;8(63):107206–107222. PubMed PMID: 29291023; PubMed Central PMCID: PMCPMC5739808. eng
   PubMedGoogle Scholar
• Horibata S, Gui G, Lack J, et al. Heterogeneity in refractory acute myeloid leukemia. Proc Natl Acad Sci U S A. 2019 May 21;116(21):10494–10503. PubMed PMID: 31064876; PubMed Central PMCID: PMCPMC6535032. eng
   PubMed Web of Science ®Google Scholar
• Parry D, Guzi T, Shanahan F, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010;9(8):2344–2353.
   PubMed Web of Science ®Google Scholar
• Paruch K, Dwyer MP, Alvarez C, et al. Discovery of dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases. ACS Med Chem Lett. 2010 Aug 12;1(5):204–208.
   PubMed Web of Science ®Google Scholar
• Baker A, Gregory GP, Verbrugge I, et al. The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res. 2016;76(5):1158–1169.
   PubMed Web of Science ®Google Scholar
• Gojo I, Sadowska M, Walker A, et al. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias [journal article]. Cancer Chemother Pharmacol. 2013 Oct 01;72(4):897–908.
   PubMed Web of Science ®Google Scholar
• Mita MM, Mita AC, Moseley JL, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies [clinical study]. Br J Cancer. 2017 Aug 31 online;117:1258. https://www.nature.com/articles/bjc2017288#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Li L, Pongtornpipat P, Tiutan T, et al. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1 [original article]. Leukemia. 2015 April 17 online;29:1702. https://www.nature.com/articles/leu201599#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Scholz A, Luecking U, Siemeister G, et al. Abstract DDT02-02: BAY 1143572: A first-in-class, highly selective, potent and orally available inhibitor of PTEFb/CDK9 currently in phase I, inhibits MYC and shows convincing anti-tumor activity in multiple xenograft models by the induction of apoptosis. Cancer Res. 2015;75(15Supplement):DDT02.
   Google Scholar
• Scholz A, Oellerich T, Hussain A, et al. Abstract 3022: BAY 1143572, a first-in-class, highly selective, potent and orally available inhibitor of PTEFb/CDK9 currently in phase I, shows convincing anti-tumor activity in preclinical models of acute myeloid leukemia (AML). Cancer Res. 2016;76(14 Supplement):3022.
   Google Scholar
• Lücking U, Scholz A, Lienau P, et al. Identification of atuveciclib (BAY 1143572), the first highly selective, clinical PTEFb/CDK9 inhibitor for the treatment of cancer. ChemMedChem. 2017;12(21):1776–1793. PubMed PMID: 28961375; eng
   PubMed Web of Science ®Google Scholar
• Luecking UT, Scholz A, Kosemund D, et al. Abstract 984: identification of potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer: from p.o. to i.v. application via scaffold hops [abstract]. Cancer Res. 2017;77(13Supplement):984.
   Google Scholar
• Byrne M, Frattini MG, Ottmann OG, et al. Phase I study of the PTEFb inhibitor BAY 1251152 in patients with acute myelogenous leukemia [abstract]. Blood. 2018;132(Suppl 1):4055.
   Web of Science ®Google Scholar
• Goh KC, Novotny-Diermayr V, Hart S, et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties [original article]. Leukemia. 2011 Aug 23 online;26:236. https://www.nature.com/articles/leu2011218#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Pallis M, Abdul-Aziz A, Burrows F, et al. The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells. Br J Haematol. 2012;159(2):191–203.
   PubMed Web of Science ®Google Scholar
• Pallis M, Burrows F, Ryan J, et al. Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget. 2017 Mar 7;8(10):16220–16232. PubMed PMID: 27092880; PubMed Central PMCID: PMCPMC5369958. eng.
   PubMedGoogle Scholar
• Meyerson M, Harlow E. Identification of G1 kinase activity for CDK6, a novel cyclin D partner. Mol Cell Biol. 1994;14(3):2077–2086.
   PubMed Web of Science ®Google Scholar
• Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-CDK complexes. Mol Cell Biol. 1998;18(2):753–761.
   PubMed Web of Science ®Google Scholar
• Harbour JW, Luo RX, Santi AD, et al. CDK phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999 Sept 17;98(6):859–869.
   PubMed Web of Science ®Google Scholar
• Flemington EK, Speck SH, Kaelin WG. E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Nat Acad Sci. 1993;90(15):6914–6918.
   PubMed Web of Science ®Google Scholar
• Helin K, Harlow E, Fattaey A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol Cell Biol. 1993;13(10):6501–6508.
   PubMed Web of Science ®Google Scholar
• Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000 Oct 1;14(19):2393–2409.
   PubMed Web of Science ®Google Scholar
• Trimarchi JM, Lees JA. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002 Jan 01;3(1):11–20.
   PubMed Web of Science ®Google Scholar
• Della Ragione F, Borriello A, Mastropietro S, et al. Expression of G1-phase cell cycle genes during hematopoietic lineage. Biochem Biophys Res Commun. 1997 Feb 03;231(1):73–76.
   PubMed Web of Science ®Google Scholar
• Chilosi M, Doglioni C, Yan Z, et al. Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia. Am J Pathol. 1998;152(1):209–217. PubMed PMID: 9422538; eng.
   PubMed Web of Science ®Google Scholar
• Malumbres M, Sotillo R, Santamarı́a D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases CDK4 and CDK6. Cell. 2004 Aug 20;118(4):493–504.
   PubMed Web of Science ®Google Scholar
• Placke T, Faber K, Nonami A, et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood. 2014;124(1):13–23
   PubMed Web of Science ®Google Scholar
• Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature. 2006 Aug 01;442(7104):818–822.
   PubMed Web of Science ®Google Scholar
• Somervaille TCP, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006 Nov 01;10(4):257–268.
   PubMed Web of Science ®Google Scholar
• Wang L, Wang J, Blaser BW, et al. Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood. 2007;110(6):2075–2083
   PubMed Web of Science ®Google Scholar
• Lopez S, Voisset E, Tisserand JC, et al. An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia. Oncotarget. 2016 Aug 9;7(32):51163–51173. PubMed PMID: 27323399; PubMed Central PMCID: PMCPMC5239466. eng.
   PubMedGoogle Scholar
• Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–1438.
   PubMed Web of Science ®Google Scholar
• Yang C, Boyson CA, Di Liberto M, et al. CDK4/6 inhibitor PD 0332991 sensitizes acute myeloid leukemia to cytarabine-mediated cytotoxicity. Cancer Res. 2015;75(9):1838–1845.
   PubMed Web of Science ®Google Scholar
• Uras IZ, Walter GJ, Scheicher R, et al. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016;127(23):2890–2902.
   PubMed Web of Science ®Google Scholar
• Fröhling S, Agrawal M, Jahn N, et al. CDK4/6 inhibitor palbociclib for treatment of KMT2A-rearranged acute myeloid leukemia: interim analysis of the AMLSG 23-14 Trial [abstract]. Blood. 2016;128(22):1608.
   Web of Science ®Google Scholar
• Marubayashi S, Park A, Noubade R, et al. FLX925 is a rationally designed FLT3, CDK4/6 inhibitor with a desirable resistance profile [abstract]. Blood. 2016;128(22):2323.
   Web of Science ®Google Scholar
• Daver N, Pollyea DA, Rizzieri DA, et al. A phase I study of FLX925, a dual FLT3 and CDK4/6 inhibitor in patients with relapsed or refractory acute myeloid leukemia (AML) [abstract]. Blood. 2017;130(Suppl 1):1343.
   Google Scholar
• Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016 Jun 9;374(23):2209–2221. PubMed PMID: 27276561; PubMed Central PMCID: PMCPMC4979995. eng
   PubMed Web of Science ®Google Scholar
• Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21;379(9825):1508–1516. PubMed PMID: 22482940; eng.
   PubMed Web of Science ®Google Scholar
• Lambert J, Pautas C, Terre C, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase 3 ALFA-0701 trial. Haematologica. 2018 Aug 3. DOI:10.3324/haematol.2018.188888. [ PubMed PMID: 30076173; eng].
   Web of Science ®Google Scholar
• Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–299.
   PubMed Web of Science ®Google Scholar
• Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–2677. PubMed PMID: 22689805
   PubMed Web of Science ®Google Scholar
• Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–1124.
   PubMed Web of Science ®Google Scholar
• Villalobos-Ortiz M, Ryan J, Mashaka TN, et al. BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics. Cell Death Differ. 2019 July 22. DOI:10.1038/s41418-019-0391-9.
   PubMed Web of Science ®Google Scholar
• Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia [article]. Sci Rep. 2016 June 10 online;6:27696. https://www.nature.com/articles/srep27696#supplementary-information.
   PubMed Web of Science ®Google Scholar
• Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 Inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–375.
   PubMed Web of Science ®Google Scholar
• Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–1117.
   PubMed Web of Science ®Google Scholar