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The Inv(16) Oncogene CBFB::MYH11 is Required for the Rurvival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow

ABSTRACT: Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, ~40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE326604 | GEO | 2026/08/13

REPOSITORIES: GEO

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The Inv(16) Oncogene CBFB::MYH11 is Required for the Survival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow

Project description:Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, ~40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.

2026-08-13 | GSE326257 | GEO

Gene Expression Profiles with Common Translocations in Acute Myeloid Leukemia (AML) using SAGE

2005-12-01 | GSE3255 | GEO

Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance

Project description:Core binding factor (CBF) acute myeloid leukemias most commonly harbor the translocations t(8;21) or inv(16). Cohesin mutations are less commonly observed in inv(16) than in t(8;21), suggesting that they may negatively impact leukemic initiation or maintenance in this setting. We used a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3 and paradoxically found that inv(16);Smc3D/+ mice have a reduced leukemic latency compared to inv(16);Smc3+/+ mice, suggesting a role for cohesin loss in leukemic initiation or maintenance. Given the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16);Smc3 D/+ HSPCs prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. We also observe an increase in Fli1 expression and enhanced Fli1 target expression in the most primitive hematopoietic stem cells using scRNA-seq, linking enhanced Fli1 activity in the inv(16);Smc3D/+ setting to leukemic initiation consistent with elevated RAS activity, which is common in inv(16) AML. We further show that Fli1 is essential for the maintenance stage of inv(16);Smc3D/+ AML. Our data demonstrate that cohesin loss drives both leukemic initiation and maintenance in inv(16) AML, identifying Fli1 as a previously unrecognized therapeutic vulnerability.

2026-07-16 | GSE329080 | GEO

Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance [scRNA-seq]

2026-07-16 | GSE286946 | GEO

Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance [ATAC-seq]

2026-07-16 | GSE286322 | GEO

Gene Expression Profiles with Common Translocations in Acute Myeloid Leukemia (AML) using SAGE

Project description:SAGE was used to profile gene expression in leukemic myeloid progenitor cells of AML patients with t(8;21), t(15;17), t(9;11) and inv(16). Keywords: SAGE analysis of gene expression in leukemic myeloid progenitor cells isolated from bone marrow Bone marrow cells from 4 patients with de novo t(9;11), 3 with treatment-related t(9;11), and 5 each with inv(16), t(15;17), t(8;21) were used for the study. Each sample contained at least 75% affected cells with no other chromosome abnormalities at cytogenetic level. Mononuclear cells were purified from bone marrow cells for each sample, and CD15+ myeloid progenitor cells were isolated from these mononuclear cells. Poly A+ RNA were isolated from CD15+ myeloid progenitor cells of each sample for SAGE tag collection.

2005-11-30 | E-GEOD-3255 | biostudies-arrayexpress

Exploring transcriptomic change in CM-Leukemia

Project description:To explore the transcriptome change in CM-leukemia, we performed RNA-seq for bone marrow mononuclear cells from CM mice at the leukemic stage and control littermate.

2026-08-09 | GSE275198 | GEO

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.

2021-09-15 | GSE184015 | GEO

CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [RNA-seq]

Project description:We recently reported the discovery of a small molecule inhibitor, AI-10-49 which can specially inhibit the protein-protein interaction between RUNX1 tumor suppressor and CBFβ-SMMHC oncogene. We also demonstrated that AI-10-49 can re-establish the RUNX1 transcriptional program in inv(16) cells and can extend the survival of inv(16) leukemic mice. To identify the transcriptional changes associated with AI-10-49, we performed RNA-seq analysis in ME-1 cells [human inv(16) leukemia cell line] treated with AI-10-49.

2018-05-02 | GSE101788 | GEO

CBFb-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia [ATAC-seq]

Project description:We recently reported the discovery of a small molecule inhibitor, AI-10-49 which can specially inhibit the protein-protein interaction between RUNX1 tumor suppressor and CBFβ-SMMHC oncogene. We also demonstrated that AI-10-49 can re-establish the RUNX1 transcriptional program in inv(16) cells and can extend the survival of inv(16) leukemic mice. To identify the changes in chromatin accessibility associated with AI-10-49, we performed ATAC-seq analysis in ME-1 cells [human inv(16) leukemia cell line] treated with AI-10-49.

2018-05-02 | GSE101790 | GEO

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