BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid–dendritic cell leukemia
Christopher A.G. Booth, Juliette M. Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G. Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M. Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A. DeCaprio, Andrew A. Lane
Christopher A.G. Booth, Juliette M. Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G. Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M. Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A. DeCaprio, Andrew A. Lane
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Research Article Hematology

BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid–dendritic cell leukemia

Abstract

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid DC neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared with other blood cancers and, in some patients, are the only obvious somatic mutation detected. This suggests that they may alone be sufficient to drive DC transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but, mechanistically, how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that, in BPDCN leukemogenesis, MYB switches from being a regulator of DC lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in patients with BPDCN increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired DC differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.

Authors

Christopher A.G. Booth, Juliette M. Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G. Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M. Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A. DeCaprio, Andrew A. Lane

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Figure 6

BPDCN cells undergo loss of MYB and cell death upon ATRA treatment.

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BPDCN cells undergo loss of MYB and cell death upon ATRA treatment. (A) ...
(A) Number of viable GFP–dTom– and GFP+dTom+ spleen cells from leukemic Cdkn2a-KO MYB::PLEKHO1 recipient mice after 2 days of 1 μM ATRA treatment, normalized to 0 μM ATRA (n = 3 from each of 6 recipient mice). (B) Number of viable GFP+dTom+ cells per femur and tibia, and per 1 mL of peripheral blood of Cdkn2a-WT MYB::PLEKHO1 secondary recipient mice, treated daily with 20–40 mg/kg ATRA for 12 days (DMSO n = 5, ATRA n = 3). (C) Number of viable human CD45+ cells per spleen of BPDCN PDX AL04 recipient NSG mice treated daily with 20 mg/kg ATRA for 28 days (DMSO, n = 5; ATRA, n = 5). (D) Number of viable CAL1 and K562 cells after 2 days of ATRA treatment at the indicated dose, normalized to 0 μM ATRA (n = 3 per condition). (E) Annexin V apoptosis analysis of CAL1 and K562 cells after 2 days of ATRA treatment at the indicated dose (n = 3 per condition). Significance tests compare proportion of apoptotic cells (annexin V+DAPI–). (F) Cell cycle analysis of CAL1 and K562 cells after 2 days of ATRA treatment at the indicated dose (n = 3 per condition). Significance tests compare proportion of cells in G1. (G) Median fluorescence intensity for CD11b APC and CD11c APC-Cy7 in CAL1 and K562 cells after 2 days of ATRA treatment at the indicated dose (n = 3 per condition). (H) Western blots showing MYB expression in CAL1 and K562 after 2 days of ATRA treatment at the indicated dose. (I) Western blots showing MYB and MYB::ZFAT expression in BPDCN PDX AL04 and AL05 cells after 2 days of ATRA treatment at the indicated dose. (A–G) Data represent mean ± SEM. Significance determined by 2-tailed t test (A–C, and F) or 1-way ANOVA with Tukey correction for multiple comparisons (D, E, and G). *P <0.05, ***P <0.001.