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1. WO2020118168 - METHODS FOR DETECTING ACUTE MYELOID LEUKEMIA

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CLAIMS

1. A method for detecting the presence of AML-associated mutations in a nucleic acid sample obtained from a subject comprising sequencing the nucleic acid sample to detect the presence of a mutation in one or more genes selected from the group consisting of SRSF2, U2AF1, and JAK2, wherein the subject does not exhibit AML symptoms or has not been diagnosed as having AML.

2. The method of claim 1, further comprising detecting the presence of a mutation in SF3B1, DNMT3A, TET2, IDH2, IDH1, TP53, or any combination thereof

3. A method for detecting the presence of AML-associated mutations in a nucleic acid sample obtained from a subject comprising sequencing the nucleic acid sample to detect the presence of a mutation in one or more genes selected from the group consisting of SRSF2, DNMT3A, TET2, IDH2, IDH1, TP53, SF3B1, U2AF1, and JAK2, wherein the subject does not exhibit AML symptoms or has not been diagnosed as having AML.

4. The method of any one of claims 1-3, wherein the nucleic acid sample comprises one or more of genomic DNA, RNA, cDNA, cell-free DNA (cfDNA), cell-free RNA (cfRNA), and an exosome-associated nucleic acid.

5. The method of any one of claims 1-4, wherein the nucleic acid sample is a blood sample, a plasma sample, or a serum sample.

6. The method of any one of claims 1-5, wherein the nucleic acid sample is sequenced using next-generation sequencing, Sanger sequencing, whole exome sequencing, targeted exome sequencing, error-corrected sequencing, augmented exome sequencing, whole genome sequencing, mRNA-seq or whole transcriptome RNA-seq.

7. A method for predicting the risk of AML in a subject prior to the onset of AML symptoms comprising detecting the presence of one or more mutations in SRSF2, U2AF1, and/or JAK2 in a biological sample obtained from the subject, wherein the subject has not been diagnosed as having AML.

8. A method for predicting the onset of AML symptoms in a subject that has not been diagnosed as having AML comprising detecting the presence of one or more mutations in SRSF2, U2AF1, and/or JAK2 in a biological sample obtained from the subject, wherein the subject has not been diagnosed as having AML.

9. The method of claim 7 or 8, further comprising detecting the presence of a mutation in SF3B1, DNMT3A, TET2, IDH2, IDH1, TP53, or any combination thereof

10. The method of any one of claims 7-9, wherein the one or more mutations in SRSF2, U2AF1, and/or JAK2, and optionally SF3B1, DNMT3A, TET2, IDH2, IDH1, and/or TP53 are detected using PCR, Northern blots, Southern blots, microarray, dot or slot blots, in situ hybridization, electrophoresis, chromatography, mass spectroscopy, sedimentation, next-generation sequencing, Sanger sequencing, whole exome sequencing, targeted exome sequencing, error-corrected sequencing, augmented exome sequencing, whole genome sequencing, mRNA-seq or whole transcriptome RNA-seq.

11. The method of claim 10, wherein PCR comprises Real-time quantitative PCR (RQ-PCR), digital PCR, or reverse transcriptase PCR (RT-PCR).

12. The method of any one of claims 7-11, further comprising detecting 2-hydroxyglutarate levels in the biological sample.

13. The method of any one of claims 7-12, wherein the biological sample is a blood sample, a plasma sample, or a serum sample.

14. The method of any one of claims 7-13, wherein the biological sample comprises one or more of genomic DNA, RNA, cDNA, cell-free DNA (cfDNA), cell-free RNA (cfRNA), and an exosome-associated nucleic acid.

15. The method of any one of claims 1-14, wherein the mutation in SRSF2, DNMT3A, TET2, IDH2, IDH1, TP53, SF3B1, U2AF1, or JAK2 is a frameshift mutation, a missense mutation, a nonsense mutation, a splice site mutation, a duplication, an insertion mutation, and a deletion mutation.

16. The method of any one of claims 1-15, further comprising detecting the presence of a mutation in one or more genes selected from the group consisting of ASXL1, ASXL2,

BRAF, CALR, CARDl l, CBL, CBLB, CBLC, CEBPA, CREBBP, CSF3R, CUX1, ETV6, EZH2, FLT1, FLT3, GATA1, GATA2, GNAS, HRAS, IKZF1, JAK1, KDM6A, KIT,

KRAS, NOTCH1, NPM1, NRAS, PAX5, PHF6, RAD21, RUNX1, SETBP1,

SF3B1,STAG1, STAT6, and TET1.

17. The method of any one of claims 2-6, or 9-16, wherein the mutation in DNMT3A is selected from the group consisting of p.Leu731del, p.Gly543Cys, p.Phe752Ser, p.Arg635Gly, p.Arg882Cys, p.Trp306Cys, p.Glnl 10AlafsTerl4, p.Gly726Val, p.Phe731Leu, p.Leu905Pro,

p.Arg736His, p.Gly308Arg, p.Pro904Leu, p.Arg882His, p.Ser337Leu, p.Lys766ArgfsTerl3, p.Arg320Ter, p.Pro777Leu, p.Tyr533Cys, p.Arg326Cys, p.Phe755Ser, p.Arg882Ser, p.Val657Met, p.Trp313Ter, p.Arg326His, p.Tyr533Ter, p.Phe336SerfsTer9, p.Arg882Pro, p.Val328Phe, p.Arg598Ter, p.Ser770Leu, p.Thr862Ile, p.His873Pro, p.Cys557Gly, p.Arg688His, p.Gly413SerfsTer238, p.Val759TrpfsTer20, p.Phe303SerfsTerl3,

p.Arg771Ter, p.Glu774Asp, p.Pro416LeufsTer235, p.Cys710AlafsTer69,

p.Phe751SerfsTer28, p.Gly293Arg, p.Gly728Asp, p.Trp330Ter, p.Pro743His, p.Trp860Ter, p.Leu737Arg, p.Ala254HisfsTer62, p.Val830Ter, p.Gly706Glu, p.Gln485ArgfsTerl66, p.Pro804Leu, p.Ala368Asp, p.Tyr528Asn, p.Phe732Ser, p.Arg736Cys, p.Tyr536Ter, p.Val296Met, p.Trp795Ter, p.Trp698Gly, p.Asp531Asn, p.Thr503AsnfsTer43, p.Pro904Gln, p.Tyr735Cys, p.Phe848Ser, p.Phe794LeufsTer4, p.Lys906Glu, p.Ile670HisfsTer43, p.Ile705Thr, p.Arg635Trp, p.Val895Met, p.Trp409Ter, p.Leu605AspfsTer7, p.Glu725Ter, p.Ser393ValfsTerl4, p.Gly796ValfsTer6, p.Cys537Arg, p.Phe414Val. p.Gln816AlafsTer42, p.Ala368Thr, p.Trp314Ter, p.Gly550Arg, p.Glu561Ter, p.Glu733Gly, p.Tyr908Cys, p.Pro849LeufsTer4, p.Ala910Pro, p.Trp860Arg, p.Cys666TrpfsTer39,

p.Arg458GlyfsTerl93, p.Trp305Gly, p.Asn797ThrfsTer5, p.Ala368Val,

p.Val502AspfsTer43, p.Ile780Thr, p.Met852IlefsTer29, p.Pro849Ser, p.Trp601Ter, p.Met761Val, p.Asn797Lys, p.Arg899Cys, p.Arg301Trp, and p.Arg749Gly.

18. The method of any one of claims 2-6 or 9-17, wherein the mutation in IDH1 is p.Argl32Cys or p.Argl32Gly.

19. The method of any one of claims 2-6 or 9-18, wherein the mutation in IDH2 is p.Argl40Gln, p.Argl40His, or p.Argl40Trp.

20. The method of any one of claims 1-19, wherein the mutation in JAK2 is p.Val617Phe, p.Gly48Glu, or p.Glu814Gly.

21. The method of any one of claims 2-6 or 9-20, wherein the mutation in SF3B1 is selected from the group consisting of p. Arg625Leu, p.Lys790Glu, p.Gly742Asp,

p.Lys700Glu, p.Ala263Val, p.Lys666Asn, p.Ala744Val, p.His662Asp, and p.Arg625Cys.

22. The method of any one of claims 1-21, wherein the mutation in SRSF2 is selected from the group consisting of p.Pro95His, p.Pro95Leu, p.Pro95Arg, and p.Pro95Thr.

23. The method of any one of claims 2-6 or 9-22, wherein the mutation in TET2 is selected from the group consisting of p.Gln644Ter, p.Glnl510Ter, p.Serl67PhefsTer4, p.Hisl912Tyr, p.Glnl80Ter, p.Glnl523Ter, p.Prol356_Glul357del, p.Glul318Gly,

p.Cysl263Arg, p.Glul874Gln, p.Asnl40Ser, p.Asnl40ThrfsTer8, p.Gln892Ter,

p.Ilel 105TyrfsTer25, p.Leul780SerfsTer38, p.Val291GlyfsTer2, p.Asp302ValfsTer6, p.Gln706Ter, p.Val291TrpfsTer2, p.Glu320AsnfsTer27, p.His786LeufsTer27,

p.Leul515AlafsTer62, p.Asnl489MetfsTer82, p.Argl451GlyfsTer7, p.Met695CysfsTer5, p.Leul 151Pro, p.Val647TrpfsTer53, p.Tyrl337Ter, p.Cysl378Tyr, p.Ala727HisfsTer23, p.Glul320ArgfsTer43, p.Trp954LeufsTerl8, p.Tyrl 148LeufsTer9, p.Hisl881Tyr, p.Vall900Gly, p.Leul 51 1TrpfsTer60, p.Glu537Ter, p.Gln764Ter, p.Aspl427ValfsTer22, p.Leu920SerfsTer2, p.Gln740Ter, p.Prol594GlnfsTer37, p.Ilel873Asn, p.Glyl361Asp, p.Leu500Ter, p.Gly773Ter, p.Gln321Ter, p.Gln745Ter, p.Aspl858SerfsTerlO,

p.Alal l58Val, p.Serl494Ter, p.Cysl875Gly, p.Leu719Ter, p.Alal876Val, p.Gln705Ter, p.Serl870Leu, p.Hisl386Asp, p.Glnl414His, p.Asn442LysfsTerl9, p.Lys664Glu, p.Argl452Ter, p.Serl898Pro, p.Cysl378Arg, p.Gln734Ter, p.Hisl904Leu,

p.Thr556AsnfsTerl 1, p.Cysl263Tyr, p.Prol644HisfsTer51, p.Gly641ArgfsTer40, p.Glul879Val, p.Hisl904Arg, p.Alal512Val, p.Hisl904Gln, p.Metl333TyrfsTer6, p.Ilel 160TyrfsTer2, p.Argl359Ser, p.Asn258MetfsTer35, p.Lysl299Ter,

p.Alal 174LysfsTer53, p.Asn442ThrfsTer5, p.Argl516Ter, p.Glyl275Arg, p.Ilel873Thr, p.Trpl847Ter, p.Thr229AsnfsTer25, p.Tyrl294Ter, p.Argl712Ter, p.Tyrl902Cys, p.Leu200ThrfsTer2, p.Glyl282Cys, p.Aspl376Gly, p.Vall056LeufsTerl0,

p.Cys973LeufsTer3, p.Glnl547LeufsTerl9, and p.Leul276TrpfsTer87.

24. The method of any one of claims 2-6 or 9-23, wherein the mutation in TP53 is selected from the group consisting of p.Leu93ArgfsTer30, p.Arg337Cys, p.Glnl67Ter, p.Leul45Pro, p.Lys321Ter, p.GlnlOOTer, p.Arg248Trp, p.Arg273His, p.Alal61Thr, p.Argl75Gly, p.Tyrl63His, p.Tyr236His, p.Cys275Tyr, p.Ilel95Ser, p.Prol28LeufsTer42, p.Tyr220Cys, p.Val272Met, p.Cys242Tyr, p.Asn29ThrfsTerl5, p.Arg333ValfsTerl2, p.Met246Ile, p.Pro278His, p.Asn239Ser, p.Vall43Met, p.Argl75His, p.Thrl55Asn, p.Tyr234Cys, p.Phel09SerfsTerl4, and p.Cys275Phe.

25. The method of any one of claims 1-24, wherein the mutation in U2AF1 is selected from the group consisting of p.Argl56His, p.Glnl57Arg, p.Tyrl 58dup, and p.Glnl57Pro.

26. The method of any one of claims 1-25, wherein the AML symptoms are selected from the group consisting of fever, fatigue, irregular heartbeat, dizziness, bone pain, frequent nosebleeds, bleeding and swollen gums, bruising on skin, loss of appetite, excessive sweating, shortness of breath, unexplained weight loss, headaches, diarrhea, menorrhagia, slurred speech, confusion, abdominal swelling, pale skin, seizures, vomiting, loss of balance, facial numbness, and blurred vision.

27. The method of any one of claims 1-26, wherein the AML has a subtype selected from the group consisting of MO, Ml, M2, M3, M4, M5, M6, M7 and M4Eo.

28. A method for selecting a subject at risk for AML for treatment with an AML therapy comprising

(a) detecting the presence of one or more mutations in SRSF2, U2AF1, and JAK2 in a biological sample obtained from the subject; and

(b) selecting the subject for treatment with an AML therapy,

wherein the subject does not exhibit AML symptoms, and wherein the AML therapy comprises one or more of chemotherapeutic agents, FLT3 inhibitors, IDH inhibitors, Gemtuzumab ozogamicin, BCL-2 inhibitors, Hedgehog pathway inhibitors, All-trans-retinoic acid, and Arsenic trioxide.

29. A method for selecting a subject at risk for AML for treatment with an AML therapy comprising

(a) detecting the presence of one or more mutations in SRSF2, DNMT3 A, TET2, IDH2, IDHl, TP53, SF3B1, U2AF1, and JAK2 in a biological sample obtained from the subject; and

(b) selecting the subject for treatment with an AML therapy,

wherein the subject does not exhibit AML symptoms, and wherein the AML therapy comprises one or more of chemotherapeutic agents, FLT3 inhibitors, IDH inhibitors, Gemtuzumab ozogamicin, BCL-2 inhibitors, Hedgehog pathway inhibitors, All-trans-retinoic acid, and Arsenic trioxide.

30. A method for preventing or delaying the onset of AML symptoms in a subject at risk for AML comprising administering an effective amount of an AML therapy to the subject, wherein the subject harbors a mutation in one or more genes selected from the group consisting of SRSF2, DNMT3A, TET2, IDH2, IDHl, TP53, SF3B1, U2AF1, and JAK2, and wherein the AML therapy comprises one or more of chemotherapeutic agents, FLT3 inhibitors, IDH inhibitors, Gemtuzumab ozogamicin, BCL-2 inhibitors, Hedgehog pathway inhibitors, All-trans-retinoic acid, and Arsenic trioxide.

31. The method of claim 30, wherein the AML symptoms are selected from the group consisting of fever, fatigue, irregular heartbeat, dizziness, bone pain, frequent nosebleeds, bleeding and swollen gums, bruising on skin, loss of appetite, excessive sweating, shortness of breath, unexplained weight loss, headaches, diarrhea, menorrhagia, slurred speech, confusion, abdominal swelling, pale skin, seizures, vomiting, loss of balance, facial numbness, and blurred vision.

32. The method of any one of claims 28-31, wherein the chemotherapeutic agents comprise one or more of cytarabine, an anthracycline drug, cladribine, fludarabine, mitoxantrone, etoposide (VP- 16), 6-thioguanine (6-TG), hydroxyurea, corticosteroid drugs, Methotrexate (MTX), 6-mercaptopurine (6-MP), azacitidine, and decitabine.

33. The method of any one of claims 28-32, wherein the FLT3 inhibitors are selected from the group consisting of midostaurin, lestaurtinib, sunitinib, sorafenib, gilteritinib, quizartinib, crenolanib, tandutinib, ponatinib, PLX3397, KW-2449, and ASP2215.

34. The method of any one of claims 28-33, wherein the IDH inhibitors are selected from the group consisting of AG-881 (Vorasidenib), ivosidenib, enasidenib, BAY-1436032, AGI-5198, IDH305, AGI-6780, FT-2102, HMS-101, MRK-A, and GSK321.

35. The method of any one of claims 28-34, wherein the BCL-2 inhibitors are selected from the group consisting of ABT-199 (venetoclax), HA14-1, obatoclax (GX-15-070), ABT-737, GDC-0199, and ABT-263 (navitoclax).

36. The method of any one of claims 28-35, wherein the Hedgehog pathway inhibitors are selected from the group consisting of glasdegib, vismodegib, sonidegib, GANT-58 and GANT-61, Arsenic Trioxide, RU-SKI 43, and 5E1 monoclonal antibody.