Description

Strain Information

Former Names STOCK Mll1tm2(MLLT3)Thr/KsyJ    (Changed: 09-MAY-13 ) B6.129P2(Cg)-Mll1tm2(MLLT3)Thr/KsyJ    (Changed: 29-DEC-11 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System +/+ sibling x Heterozygote         (Female x Male)   26-SEP-11 Species laboratory mouse Generation N5+N4 (27-DEC-12) Generation Definitions   Donating Investigator John H Kersey,   Masonic Cancer Center (Univ of Minn)

Description
The Mll-AF9 knock-in allele encodes a MLL-AF9 fusion protein that mimics the t(9;11)(p22;q23) translocation identified in acute myeloid leukemia (AML) patients. While homozygous mice are not viable, heterozygotes are viable and fertile but females are poor mothers and may not survive pregnancy. Expression of the MLL-AF9 fusion protein results in development of leukemia beginning around six months of age; almost all of which are AMLs. Detectable proliferation of myeloid cells is observed in bone marrow by as little as six days after birth, and this early accumulation of myeloid precursors likely confers a greater chance of acquiring secondary mutations that cooperate in the appearance of overt cancer. These Mll-AF9 knock-in mice may be useful for studying hematopoietic development, cancer, and AML.

Development
These Mll-AF9 knock-in mice were generated in the laboratory of Dr. Terence H Rabbitts (Medical Research Council Laboratory of Molecular Biology, Cambridge UK and currently Leeds Institute of Molecular Medicine, Leeds UK). A targeting vector was used for in-frame fusion of a 3'-terminal human AF9 cDNA sequence (nucleotide 1634 to the translation terminus of the MLLT3 locus) and an SV40 poly(A) signal into the BamHI site of exon 8 (corresponding to nucleotide 3987) of the targeted gene. This also inserted a MC1-neo-poly(A) cassette immediately downstream of the fusion segment. The targeting construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with C57BL/6 and/or wildtype siblings and/or outbred MF1 females. Mll-AF9 knock-in mice were subsequently bred with C57BL/6 mice for an unknown number of generations and then sent to the laboratory of Dr. John H Kersey (Masonic Cancer Center, University of Minnesota). There, the mutant males were bred with C57BL/6NCrl females for four generations, and next maintained by breeding mutant males with wildtype female siblings for approximately 20 generations prior to arrival at The Jackson Laboratory. The donating investigator reports both agouti and black coat colors (see SNP note below). Upon arrival, mice were bred with C57BL/6NJ inbred mice (Stock No. 005304) for at least one generation to establish the mutant colony. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6 genetic background.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. At least 3 markers are segregating, suggesting an incomplete backcross. Also, 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed genetic background.

Control Information

	Control
	Wild-type from the colony
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Kmt2a

021296	B6;129X1-Kmt2atm2Sjk/JjdhJ
021297	STOCK Kmt2atm1SjkJjdh/J

View Strains carrying other alleles of Kmt2a     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Leukemia, Acute Myeloid; AML

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Hairy Elbows, Short Stature, Facial Dysmorphism, and Developmental Delay   (KMT2A) Myeloid/Lymphoid or Mixed Lineage Leukemia Gene; MLL   (KMT2A)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Kmt2a^{tm2(MLLT3)Thr}/Kmt2a⁺

        involves: 129P2/OlaHsd

• tumorigenesis
• leukemia
  • predominantly acute myeloid leukemia (AML) involving immature myeloblasts and extramedullary leukemia   (MGI Ref ID J:56340)
  • a minority of the observed leukemia is acute lymphoblastic leukemia (ALL)   (MGI Ref ID J:56340)
  • 50% of heterozygotes succumb to AML at 5 months of age   (MGI Ref ID J:56340)
  • almost all mice develop malignancy within 1 1/2 years   (MGI Ref ID J:56340)
• hematopoietic system phenotype
• abnormal hematopoiesis
  • abnormal hematopoietic differentiation resulting in an accumulation of Mac-1/Gr-1 double-positive mature myeloid cells in the bone marrow preceded the onset of AML, as early as 6 days of age   (MGI Ref ID J:56340)
• enlarged spleen   (MGI Ref ID J:56340)
• immune system phenotype
• enlarged spleen   (MGI Ref ID J:56340)
• liver/biliary system phenotype
• enlarged liver   (MGI Ref ID J:56340)
• renal/urinary system phenotype
• pale kidney   (MGI Ref ID J:56340)

Kmt2a^{tm2(MLLT3)Thr}/Kmt2a^{tm2(MLLT3)Thr}

        involves: 129P2/OlaHsd

• mortality/aging
• prenatal lethality   (MGI Ref ID J:56340)

Kmt2a^{tm2(MLLT3)Thr}/Kmt2a^{tm2(MLLT3)Thr}

        involves: 129P2/OlaHsd * C57BL/6 * FVB

• hematopoietic system phenotype
• abnormal blood cell morphology/development
  • immature cells are found in the blood   (MGI Ref ID J:110241)
• • abnormal hematopoiesis
    • bone marrow myeloid pro-B cell colony forming units in vivo are significantly higher than in wild-type and Mll1^tm1(AFF1)Ksy   (MGI Ref ID J:110241)
    • predominantly type I myeloid colonies are found   (MGI Ref ID J:110241)
  • • increased leukocyte cell number
      • 7.3x10³+/-1.3x10³/uL compared to 3.9x10³+/-1.0 x10³/uL in wild-type mice   (MGI Ref ID J:110241)
      • moribund mice have increased white blood cell counts (225.1 x10³+/-42.4 x10³uL compared to 2.4 x10³+/-0.2 x10³uL in wild-type mice)   (MGI Ref ID J:110241)
    • • increased neutrophil cell number
        • 7.3x10³+/-1.3x10³/uL compared to 3.9x10³+/-1.0 x10³/uL in wild-type mice   (MGI Ref ID J:110241)
        • moribund mice have increased white blood cell counts (225.1 x10³+/-42.4 x10³uL compared to 2.4 x10³+/-0.2 x10³uL in wild-type mice)   (MGI Ref ID J:110241)
    • increased pro-B cell number
      • pro-B cell colony forming units in vivo are significantly higher than in wild-type mice   (MGI Ref ID J:110241)
• tumorigenesis
• B cell derived lymphoma
  • in one moribund mice follicular B-cell lymphoma with myeloid proliferative disorder was observed   (MGI Ref ID J:110241)
• leukemia
  • myeloproliferative disorders (MPD)-like myeloid leukemia is found in moribund mice   (MGI Ref ID J:110241)
  • leukemic infiltration of the spleen, bone marrow, liver, lymph nodes, and Peyer patches is observed   (MGI Ref ID J:110241)
• malignant tumors
  • 37 of 60 mice developed hematologic malignancies with a mean time to development of 220 days   (MGI Ref ID J:110241)
  • malignant cells exhibit a varying degree of differentiation from blast cells to cells with maturation into segmented neutrophils   (MGI Ref ID J:110241)
• craniofacial phenotype
• abnormal facial morphology
  • mice have short faces   (MGI Ref ID J:110241)
• • pointed snout   (MGI Ref ID J:110241)
• big ears
  • less severe than in Mll1^tm1(AFF1)Ksy homozygotes   (MGI Ref ID J:110241)
• growth/size phenotype
• decreased body size
  • mice are small at birth   (MGI Ref ID J:110241)
• • decreased body weight
    • at 5 weeks, mice weigh 13.6g compared to wild-type mice that weigh 17.4g   (MGI Ref ID J:110241)
• immune system phenotype
• increased leukocyte cell number
  • 7.3x10³+/-1.3x10³/uL compared to 3.9x10³+/-1.0 x10³/uL in wild-type mice   (MGI Ref ID J:110241)
  • moribund mice have increased white blood cell counts (225.1 x10³+/-42.4 x10³uL compared to 2.4 x10³+/-0.2 x10³uL in wild-type mice)   (MGI Ref ID J:110241)
• • increased neutrophil cell number
    • 7.3x10³+/-1.3x10³/uL compared to 3.9x10³+/-1.0 x10³/uL in wild-type mice   (MGI Ref ID J:110241)
    • moribund mice have increased white blood cell counts (225.1 x10³+/-42.4 x10³uL compared to 2.4 x10³+/-0.2 x10³uL in wild-type mice)   (MGI Ref ID J:110241)
• increased pro-B cell number
  • pro-B cell colony forming units in vivo are significantly higher than in wild-type mice   (MGI Ref ID J:110241)
• hearing/vestibular/ear phenotype
• big ears
  • less severe than in Mll1^tm1(AFF1)Ksy homozygotes   (MGI Ref ID J:110241)
• cellular phenotype
• increased pro-B cell number
  • pro-B cell colony forming units in vivo are significantly higher than in wild-type mice   (MGI Ref ID J:110241)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cancer Research
Increased Tumor Incidence
      Leukemia
Oncogenes

Developmental Biology Research
Internal/Organ Defects
      hematopoietic defects
Lymphoid Tissue Defects
      hematopoietic defects

Hematological Research
Hematopoietic Defects
Immunological Defects

Immunology, Inflammation and Autoimmunity Research
Lymphoid Tissue Defects
      hematopoietic development
      myeloid hyperplasia

Research Tools
Cancer Research
      Leukemia
      monoclonal antibodies, myeloma and hybridoma production
      myeloma and hybridoma production
Hematological Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Kmt2atm2(MLLT3)Thr
Allele Name		targeted mutation 2, Terence H Rabbitts
Allele Type		Targeted (knock-in)
Common Name(s)		Mll-AF9+; Mll1tm2Thr; Mllaf9;
Mutation Made By		Terence Rabbitts,   Leeds Institute of Molecular Med (LIMM)
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14
ES Cell Line Strain		129P2/OlaHsd
Expressed Gene		MLLT3, myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 3, human
Molecular Note		Sequence encoding a 3' portion of human MLLT3 extending from nucleotide 1634 to the translation terminus replaced a 3' portion of murine Mll exon 8. A downstream neo cassette was also included in the targeting vector for selection. The resultant fusion product putatively recapitulates the MLL/MLLT3 protein produced in patients with the acute myeloid leukamia (AML) associated transloaction T(9;11)(p22;q23). [MGI Ref ID J:75959]
Gene Symbol and Name		Kmt2a, lysine N-methyltransferase 2A
Chromosome		9
Gene Common Name(s)		ALL-1; All1; CXXC7; HRX; HTRX1; MLL; MLL/GAS7; MLL1A; Mll; Mll1; TET1-MLL; TRX1; WDSTS; acute lymphocytic leukemia; myeloid/lymphoid or mixed-lineage leukemia; myeloid/lymphoid or mixed-lineage leukemia 1; trithorax Drosophila;

Genotyping

Genotyping Information

Genotyping Protocols

Mll1^tm2Thr STD PCR, Melt Curve Analysis
Mll1^tm2Thr STD PCR, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Corral J; Lavenir I; Impey H; Warren AJ; Forster A; Larson TA; Bell S; McKenzie AN; King G; Rabbitts TH. 1996. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85(6):853-61. [PubMed: 8681380]  [MGI Ref ID J:75959]

Lane PW. 1968. New allele of diabetes. Mouse News Lett 38:24.  [MGI Ref ID J:13477]

Additional References

Kmt2a^{tm2(MLLT3)Thr} related

Bergerson RJ; Collier LS; Sarver AL; Been RA; Lugthart S; Diers MD; Zuber J; Rappaport AR; Nixon MJ; Silverstein KA; Fan D; Lamblin AF; Wolff L; Kersey JH; Delwel R; Lowe SW; O'Sullivan MG; Kogan SC; Adams DJ; Largaespada DA. 2012. An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. Blood 119(19):4512-23. [PubMed: 22427200]  [MGI Ref ID J:185178]

Chen W; Kumar AR; Hudson WA; Li Q; Wu B; Staggs RA; Lund EA; Sam TN; Kersey JH. 2008. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer Cell 13(5):432-40. [PubMed: 18455126]  [MGI Ref ID J:134770]

Chen W; Li Q; Hudson WA; Kumar A; Kirchhof N; Kersey JH. 2006. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Blood 108(2):669-77. [PubMed: 16551973]  [MGI Ref ID J:110241]

Chen W; O'Sullivan MG; Hudson W; Kersey J. 2011. Modeling human infant MLL leukemia in mice: leukemia from fetal liver differs from that originating in postnatal marrow. Blood 117(12):3474-5. [PubMed: 21436082]  [MGI Ref ID J:170308]

Dobson CL; Warren AJ; Pannell R; Forster A; Lavenir I; Corral J; Smith AJ; Rabbitts TH. 1999. The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. EMBO J 18(13):3564-74. [PubMed: 10393173]  [MGI Ref ID J:56340]

Dorrance AM; Liu S; Yuan W; Becknell B; Arnoczky KJ; Guimond M; Strout MP; Feng L; Nakamura T; Yu L; Rush LJ; Weinstein M; Leone G; Wu L; Ferketich A; Whitman SP; Marcucci G; Caligiuri MA. 2006. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J Clin Invest 116(10):2707-16. [PubMed: 16981007]  [MGI Ref ID J:115001]

Kim WI; Matise I; Diers MD; Largaespada DA. 2009. RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia. Blood 113(5):1086-96. [PubMed: 18952898]  [MGI Ref ID J:144858]

Kumar AR; Hudson WA; Chen W; Nishiuchi R; Yao Q; Kersey JH. 2004. Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Blood 103(5):1823-8. [PubMed: 14615372]  [MGI Ref ID J:88494]

Lobato MN; Metzler M; Drynan L; Forster A; Pannell R; Rabbitts TH. 2008. Modeling chromosomal translocations using conditional alleles to recapitulate initiating events in human leukemias. J Natl Cancer Inst Monogr (39):58-63. [PubMed: 18648005]  [MGI Ref ID J:140415]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous males may be bred with wildtype siblings or C57BL/6NJ inbred mice (Stock No. 005304). Homozygous mice are not viable and heterozygous females are poor mothers and may not survive pregnancy.
Mating System	+/+ sibling x Heterozygote         (Female x Male)   26-SEP-11
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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