IP Library › Granted Patent US 12,559,800
Granted Patent B2
US 12,559,800 · App. 17/638,740 · Granted Feb 24, 2026

KMT2A-MAML2 fusion molecules and uses thereof

Inventor: Erik Williams (Boston, MA)
Assignee: Foundation Medicine, Inc.
C12Q1/6886G01N33/574C12Q2600/156C12Y201/01G01N2333/4706G01N2333/91017
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Quick Facts
Patent No.
US 12,559,800
App. No.
17/638,740
Granted
Feb 24, 2026
Kind
B2
Abstract

The present disclosure provides KMT2A-MAML2 fusion nucleic acid molecules, and KMT2A-MAML2 fusion polypeptides, as well as methods, kits and reagents for detecting such KMT2A-MAML2 fusion nucleic acid molecules and KMT2A-MAML2 fusion polypeptides. The disclosure also provides methods for evaluating, identifying, assessing, and/or treating an individual having a cancer, such an epithelial neoplasm or a thymoma.

Claims (73)

1 . A method of treating a thymoma in an individual, comprising administering to the individual an effective amount of an anti-cancer therapy, wherein the thymoma comprises a KMT2A-MAML2 fusion nucleic acid molecule or a KMT2A-MAML2 fusion polypeptide;

wherein the anti-cancer therapy is an agent that inhibits activity or expression of the KMT2A-MAML2 polypeptide, a NOTCH pathway inhibitor, or an agent that inhibits activity or expression of epidermal growth factor receptor (EGFR).

2 . A method of treating a thymoma in an individual, comprising, responsive to knowledge of a KMT2A-MAML2 fusion nucleic acid molecule or of a KMT2A-MAML2 fusion polypeptide in a sample from the individual, administering to the individual an effective amount of an anti-cancer therapy;

wherein the anti-cancer therapy is an agent that inhibits activity or expression of the KMT2A-MAML2 polypeptide, a NOTCH pathway inhibitor, or an agent that inhibits activity or expression of epidermal growth factor receptor (EGFR).

3 . A method of treating a thymoma in an individual, comprising:

(a) acquiring knowledge of a KMT2A-MAML2 fusion nucleic acid molecule or a KMT2A-MAML2 fusion polypeptide in a sample from the individual; and

(b) administering to the individual an effective amount of an anti-cancer therapy, wherein the anti-cancer therapy is an agent that inhibits activity or expression of the KMT2A-MAML2 polypeptide, a NOTCH pathway inhibitor, or an agent that inhibits activity or expression of epidermal growth factor receptor (EGFR).

4 . The method of claim 3 , wherein acquiring knowledge comprises detecting the KMT2A-MAML2 fusion nucleic acid molecule or the KMT2A-MAML2 fusion polypeptide in a sample from the individual.

5 . The method of claim 3 , wherein the method comprises acquiring knowledge of the KMT2A-MAML2 fusion nucleic acid molecule in the sample from the individual, and wherein the KMT2A-MAML2 fusion nucleic acid molecule comprises:

exon 7 or a portion thereof, intron 7 or a portion thereof, exon 8 or a portion thereof, intron 8 or a portion thereof, exon 9 or a portion thereof, intron 9 or a portion thereof, exon 10 or a portion thereof, intron 10 or a portion thereof, exon 11 or a portion thereof, or intron 11 or a portion thereof, of KMT2A and intron 1 or a portion thereof, exon 2 or a portion thereof, intron 2 or a portion thereof, exon 3 or a portion thereof, intron 3 or a portion thereof, or exon 4, of MAML2; and

a KMT2A-MAML2 breakpoint that fuses exon 7 or the portion thereof, intron 7 or the portion thereof, exon 8 or the portion thereof, intron 8 or the portion thereof, exon 9 or the portion thereof, intron 9 or the portion thereof, exon 10 or the portion thereof, intron 10 or the portion thereof, exon 11 or the portion thereof, or intron 11 or the portion thereof, of KMT2A to intron 1 or the portion thereof, exon 2 or the portion thereof, intron 2 or the portion thereof, exon 3 or the portion thereof, intron 3 or the portion thereof, or exon 4, of MAML2.

6 . The method of claim 5 , wherein the KMT2A-MAML2 fusion nucleic acid molecule comprises 5 or more nucleotides from exon 7, intron 7, exon 8, intron 8, exon 9, intron 9, exon 10, intron 10, exon 11, or intron 11 of KMT2A on a 5′ end of the KMT2A-MAML2 breakpoint, and 5 or more nucleotides from intron 1, exon 2, intron 2, exon 3, intron 3, or exon 4 of MAML2 on a 3′ end of the KMT2A-MAML2 breakpoint.

7 . The method of claim 3 , wherein the method comprises acquiring knowledge of the KMT2A-MAML2 fusion nucleic acid molecule in the sample from the individual, and wherein the KMT2A-MAML2 fusion nucleic acid molecule comprises:

(a) exon 7 or a portion thereof, exon 8 or a portion thereof, exon 9 or a portion thereof, exon 10 or a portion thereof, or exon 11 or a portion thereof, of KMT2A fused to exon 2 or a portion thereof, exon 3 or a portion thereof, or exon 4 or a portion thereof, of MAML2;

(b) intron 7, 8, 9, 10, or 11, or a portion thereof, of KMT2A fused to intron 1, 2, or 3, or a portion thereof, of MAML2;

(c) exon 7 or a portion thereof, exon 8 or a portion thereof, exon 9 or a portion thereof, exon 10 or a portion thereof, or exon 11 or a portion thereof, of KMT2A fused to intron 1, 2, or 3, or a portion thereof, of MAML2; or

(d) intron 7, 8, 9, 10, or 11, or a portion thereof, of KMT2A fused to exon 2 or a portion thereof, exon 3 or a portion thereof, or exon 4 or a portion thereof, of MAML2.

8 . The method of claim 3 , wherein the method comprises acquiring knowledge of the KMT2A-MAML2 fusion nucleic acid molecule in the sample from the individual, and wherein the KMT2A-MAML2 fusion nucleic acid molecule comprises a nucleotide sequence comprising, in the 5′ to 3′ direction:

(a) exons 1-6 and exon 7, or a portion of exon 7, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2;

(b) exons 1-7 and exon 8, or a portion of exon 8, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2;

(c) exons 1-8 and exon 9, or a portion of exon 9, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2;

(d) exons 1-9 and exon 10, or a portion of exon 10, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, MAML2; or

(e) exons 1-10 and exon 11, or a portion of exon 11, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2.

9 . The method of claim 3 , wherein the method comprises acquiring knowledge of the KMT2A-MAML2 fusion polypeptide in the sample from the individual, and wherein the KMT2A-MAML2 fusion polypeptide comprises:

(a) an amino acid sequence encoded by a nucleic acid molecule comprising:

exon 7 or a portion thereof, exon 8 or a portion thereof, exon 9 or a portion thereof, exon 10 or a portion thereof, or exon 11 or a portion thereof, of KMT2A and exon 2 or a portion thereof, exon 3 or a portion thereof, or exon 4, of MAML2; and

a KMT2A-MAML2 breakpoint that fuses exon 7 or the portion thereof, exon 8 or the portion thereof, exon 9 or the portion thereof, exon 10 or the portion thereof, or exon 11 or the portion thereof, of KMT2A to exon 2 or the portion thereof, exon 3 or the portion thereof, or exon 4, of MAML2; or

(b) an amino acid sequence at least about 85% identical to the KMT2A-MAML2 fusion polypeptide of (a).

10 . The method of claim 9 , wherein the KMT2A-MAML2 fusion polypeptide comprises 5 or more amino acids encoded by a 3′ end of exon 7 or the portion thereof, a 3′ end of exon 8 or the portion thereof, a 3′ end of exon 9 or the portion thereof, a 3′ end of exon 10 or the portion thereof, or a 3′ end of exon 11 or the portion thereof, of KMT2A fused to 5 or more amino acids encoded by a 5′ end of exon 2 or the portion thereof, exon 3 or the portion thereof, or exon 4, of MAML2.

11 . The method of claim 3 , wherein the method comprises acquiring knowledge of the KMT2A-MAML2 fusion polypeptide in the sample from the individual, and wherein the KMT2A-MAML2 fusion polypeptide comprises:

(a) an amino acid sequence encoded by a KMT2A-MAML2 fusion nucleic acid molecule comprising, in the 5′ to 3′ direction:

(i) exons 1-6 and exon 7, or a portion of exon 7, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2,

(ii) exons 1-7 and exon 8, or a portion of exon 8, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2,

(iii) exons 1-8 and exon 9, or a portion of exon 9, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2,

(iv) exons 1-9 and exon 10, or a portion of exon 10, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2, or

(v) exons 1-10 and exon 11, or a portion of exon 11, of KMT2A and exon 2 or a portion thereof and exons 3-5, exon 3 or a portion thereof and exons 4-5, or exons 4-5, of MAML2; or

(b) an amino acid sequence at least about 85% identical to the KMT2A-MAML2 fusion polypeptide of (a).

12 . The method of claim 9 , wherein in vivo expression of the KMT2A-MAML2 fusion polypeptide results in modulation in the expression of one or more genes in the NOTCH pathway.

13 . The method of claim 9 , wherein the KMT2A-MAML2 fusion polypeptide comprises a histone methyltransferase activity.

14 . The method of claim 9 , wherein the KMT2A-MAML2 fusion polypeptide comprises a constitutive histone methyltransferase activity.

15 . The method of claim 9 , wherein the thymoma is an adult thymoma.

16 . The method of claim 9 , wherein the thymoma has a B2 histology, a B3 histology, or a B2-B3 histology.

17 . The method of claim 9 , wherein the thymoma is a stage 2b, 4a, or 4b thymoma.

18 . The method of claim 9 , wherein the thymoma is recurrent.

19 . The method of claim 9 , wherein the thymoma is metastatic.

20 . The method of claim 9 , wherein the thymoma comprises a mutation in a gene selected from the group consisting of TP53, ARIDIA, TERT, and SF3B1.

21 . The method of claim 3 , wherein the individual has received a prior anti-cancer treatment.

22 . The method of claim 9 , wherein the individual has received a prior anti-cancer treatment comprising one or more of a chemotherapy, surgical resection, radiation, MGCD516, BBI608, paclitaxel, or sunitinib.

23 . The method of claim 3 , wherein the anti-cancer therapy is a small molecule, an antibody, or a nucleic acid.

24 . The method of claim 3 , wherein the anti-cancer therapy is an agent that inhibits activity or expression of the KMT2A-MAML2 polypeptide, or a NOTCH pathway inhibitor.

25 . The method of claim 24 , wherein the NOTCH pathway inhibitor inhibits Notch1.

26 . The method of claim 3 , wherein the anti-cancer therapy is an agent that inhibits activity or expression of epidermal growth factor receptor (EGFR).

27 . The method of claim 26 , wherein the agent is a small molecule, an antibody, or a nucleic acid.

28 . The method of claim 26 , wherein the agent is selected from the group consisting of lapatinib, gefitinib, erlotinib, cetuximab, canertinib, panitumumab, nimotuzumab, OSI-632, vandetanib, afatinib, MP-412, AEE-788, neratinib, XL-647, dacomitinib, AZD-8931, CUDC-101, and CO-1686.

29 . The method of claim 3 , wherein the sample comprises fluid, cells, or tissue.

30 . The method of claim 29 , wherein the sample comprises a tumor biopsy, blood, or a circulating tumor cell.

31 . The method of claim 3 , wherein the sample is a nucleic acid sample.

32 . The method of claim 31 , wherein the nucleic acid sample comprises mRNA, genomic DNA, circulating tumor DNA, cell-free DNA, or cell-free RNA.

33 . The method of claim 31 , wherein the KMT2A-MAML2 fusion nucleic acid molecule is detected in the sample by a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing, next-generation sequencing, a screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, sequence-specific priming (SSP) PCR, HPLC, or mass-spectrometric genotyping.

34 . The method of claim 3 , wherein the sample is a protein sample.

35 . The method of claim 34 , wherein the KMT2A-MAML2 fusion polypeptide is detected in the sample by immunoblotting, ELISA, immunohistochemistry, or mass spectrometry.

36 . The method of claim 3 , wherein the fusion nucleic acid molecule comprises a KMT2A-MAML2 breakpoint comprising:

(a) the nucleic acid sequence of SEQ ID NO: 7 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 7 fused to the nucleic acid sequence of SEQ ID NO: 8 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 8;

(b) the nucleic acid sequence of SEQ ID NO: 9 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 9 fused to the nucleic acid sequence of SEQ ID NO: 10 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 10;

(c) the nucleic acid sequence of SEQ ID NO: 11 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 11 fused to the nucleic acid sequence of SEQ ID NO: 12 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 12;

(d) the nucleic acid sequence of SEQ ID NO: 13 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 13 fused to the nucleic acid sequence of SEQ ID NO: 14 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 14;

(e) the nucleic acid sequence of SEQ ID NO: 15 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 15 fused to the nucleic acid sequence of SEQ ID NO: 16 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 16;

(f) the nucleic acid sequence of SEQ ID NO: 17 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 17 fused to the nucleic acid sequence of SEQ ID NO: 18 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 18;

(g) the nucleic acid sequence of SEQ ID NO: 19 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 19 fused to the nucleic acid sequence of SEQ ID NO: 20 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 20;

(h) the nucleic acid sequence of SEQ ID NO: 21 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 21 fused to the nucleic acid sequence of SEQ ID NO: 22 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 22;

(i) the nucleic acid sequence of SEQ ID NO: 23 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 23 fused to the nucleic acid sequence of SEQ ID NO: 24 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 24;

(j) the nucleic acid sequence of SEQ ID NO: 25 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 25 fused to the nucleic acid sequence of SEQ ID NO: 26 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 26; or

(k) the nucleic acid sequence of SEQ ID NO: 27 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 27 fused to the nucleic acid sequence of SEQ ID NO: 28 or a nucleic acid sequence at least about 85% identical to SEQ ID NO: 28.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 7, 2022
From: WILLIAMS, ERIK
To: FOUNDATION MEDICINE, INC.
Reel/Frame 059531/0522 →
Continuity (2)
Provisional Application 62894539 · Aug 30, 2019
Related Publication 20220290253A1 · Sep 15, 2022
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