Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML

A. Negri; C. Ward; A. Bucci; G. D’Angelo; P. Cauchy; A. Radesco; A. B. Ventura; D. S. Walton; M. Clarke; B. Mandriani; S. A. Pappagallo; P. Mondelli; K. Liao; G. Gargano; G. M. Zaccaria; L. Viggiano; F. M. Lasorsa; A. Ahmed; D. Di Molfetta; G. Fiermonte; M. Cives; A. Guarini; M. C. Vegliante; S. Ciavarella; J. Frampton; G. Volpe

doi:10.1038/s41419-023-06276-z

Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML

A. Negri, C. Ward, A. Bucci, G. D’Angelo, P. Cauchy, A. Radesco, A. B. Ventura, D. S. Walton, M. Clarke, B. Mandriani, S. A. Pappagallo, P. Mondelli, K. Liao, G. Gargano, G. M. Zaccaria, L. Viggiano, F. M. Lasorsa, A. Ahmed, D. Di Molfetta, G. FiermonteM. Cives, A. Guarini, M. C. Vegliante, S. Ciavarella, J. Frampton^*, G. Volpe^*

^*Corresponding author for this work

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Abstract

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

Original language	English
Article number	763
Number of pages	11
Journal	Cell death & disease
Volume	14
Issue number	11
DOIs	https://doi.org/10.1038/s41419-023-06276-z
Publication status	Published - 23 Nov 2023

Bibliographical note

Funding:
This work was supported through funding provided by the College of Medical and Dental Sciences of the University of Birmingham and the Birmingham CRUK Centre and from the Italian Ministry of Health “Ricerca Corrente 2023”.

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Negri, A., Ward, C., Bucci, A., D’Angelo, G., Cauchy, P., Radesco, A., Ventura, A. B., Walton, D. S., Clarke, M., Mandriani, B., Pappagallo, S. A., Mondelli, P., Liao, K., Gargano, G., Zaccaria, G. M., Viggiano, L., Lasorsa, F. M., Ahmed, A., Di Molfetta, D., ... Volpe, G. (2023). Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML. Cell death & disease, 14(11), Article 763. https://doi.org/10.1038/s41419-023-06276-z

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title = "Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML",

abstract = "The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.",

author = "A. Negri and C. Ward and A. Bucci and G. D{\textquoteright}Angelo and P. Cauchy and A. Radesco and Ventura, {A. B.} and Walton, {D. S.} and M. Clarke and B. Mandriani and Pappagallo, {S. A.} and P. Mondelli and K. Liao and G. Gargano and Zaccaria, {G. M.} and L. Viggiano and Lasorsa, {F. M.} and A. Ahmed and {Di Molfetta}, D. and G. Fiermonte and M. Cives and A. Guarini and Vegliante, {M. C.} and S. Ciavarella and J. Frampton and G. Volpe",

note = "Funding: This work was supported through funding provided by the College of Medical and Dental Sciences of the University of Birmingham and the Birmingham CRUK Centre and from the Italian Ministry of Health “Ricerca Corrente 2023”.",

year = "2023",

month = nov,

day = "23",

doi = "10.1038/s41419-023-06276-z",

language = "English",

volume = "14",

journal = "Cell death & disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "11",

}

Negri, A, Ward, C, Bucci, A, D’Angelo, G, Cauchy, P, Radesco, A, Ventura, AB, Walton, DS, Clarke, M, Mandriani, B, Pappagallo, SA, Mondelli, P, Liao, K, Gargano, G, Zaccaria, GM, Viggiano, L, Lasorsa, FM, Ahmed, A, Di Molfetta, D, Fiermonte, G, Cives, M, Guarini, A, Vegliante, MC, Ciavarella, S, Frampton, J & Volpe, G 2023, 'Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML', Cell death & disease, vol. 14, no. 11, 763. https://doi.org/10.1038/s41419-023-06276-z

TY - JOUR

T1 - Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML

AU - Negri, A.

AU - Ward, C.

AU - Bucci, A.

AU - D’Angelo, G.

AU - Cauchy, P.

AU - Radesco, A.

AU - Ventura, A. B.

AU - Walton, D. S.

AU - Clarke, M.

AU - Mandriani, B.

AU - Pappagallo, S. A.

AU - Mondelli, P.

AU - Liao, K.

AU - Gargano, G.

AU - Zaccaria, G. M.

AU - Viggiano, L.

AU - Lasorsa, F. M.

AU - Ahmed, A.

AU - Di Molfetta, D.

AU - Fiermonte, G.

AU - Cives, M.

AU - Guarini, A.

AU - Vegliante, M. C.

AU - Ciavarella, S.

AU - Frampton, J.

AU - Volpe, G.

N1 - Funding: This work was supported through funding provided by the College of Medical and Dental Sciences of the University of Birmingham and the Birmingham CRUK Centre and from the Italian Ministry of Health “Ricerca Corrente 2023”.

PY - 2023/11/23

Y1 - 2023/11/23

N2 - The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

AB - The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

U2 - 10.1038/s41419-023-06276-z

DO - 10.1038/s41419-023-06276-z

M3 - Article

SN - 2041-4889

VL - 14

JO - Cell death & disease

JF - Cell death & disease

IS - 11

M1 - 763

ER -

Reversal of MYB -dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML

Abstract

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