UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

S. Goyama; J. Schibler; A. Gasilina; M. Shrestha; S. Lin; K. A. Link; J. Chen; S. P. Whitman; C. D. Bloomfield; D. Nicolet; S. A. Assi; A. Ptasinska; O. Heidenreich; C. Bonifer; T. Kitamura; N. N. Nassar; J. C. Mulloy

doi:10.1038/leu.2015.275

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

S. Goyama, J. Schibler, A. Gasilina, M. Shrestha, S. Lin, K. A. Link, J. Chen, S. P. Whitman, C. D. Bloomfield, D. Nicolet, S. A. Assi, A. Ptasinska, O. Heidenreich, C. Bonifer, T. Kitamura, N. N. Nassar, J. C. Mulloy

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Abstract

The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

Original language	English
Pages (from-to)	728-739
Number of pages	12
Journal	Leukemia
Volume	30
Issue number	3
DOIs	https://doi.org/10.1038/leu.2015.275
Publication status	Published - 1 Mar 2016
Externally published	Yes

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10.1038/leu.2015.275

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Goyama, S., Schibler, J., Gasilina, A., Shrestha, M., Lin, S., Link, K. A., Chen, J., Whitman, S. P., Bloomfield, C. D., Nicolet, D., Assi, S. A., Ptasinska, A., Heidenreich, O., Bonifer, C., Kitamura, T., Nassar, N. N., & Mulloy, J. C. (2016). UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO. Leukemia, 30(3), 728-739. https://doi.org/10.1038/leu.2015.275

@article{066b5fcf2d414208b5cb60bd8fddf68a,

title = "UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO",

abstract = "The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.",

author = "S. Goyama and J. Schibler and A. Gasilina and M. Shrestha and S. Lin and Link, {K. A.} and J. Chen and Whitman, {S. P.} and Bloomfield, {C. D.} and D. Nicolet and Assi, {S. A.} and A. Ptasinska and O. Heidenreich and C. Bonifer and T. Kitamura and Nassar, {N. N.} and Mulloy, {J. C.}",

note = "Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

month = mar,

day = "1",

doi = "10.1038/leu.2015.275",

language = "English",

volume = "30",

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Goyama, S, Schibler, J, Gasilina, A, Shrestha, M, Lin, S, Link, KA, Chen, J, Whitman, SP, Bloomfield, CD, Nicolet, D, Assi, SA, Ptasinska, A, Heidenreich, O, Bonifer, C, Kitamura, T, Nassar, NN & Mulloy, JC 2016, 'UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO', Leukemia, vol. 30, no. 3, pp. 728-739. https://doi.org/10.1038/leu.2015.275

TY - JOUR

T1 - UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

AU - Goyama, S.

AU - Schibler, J.

AU - Gasilina, A.

AU - Shrestha, M.

AU - Lin, S.

AU - Link, K. A.

AU - Chen, J.

AU - Whitman, S. P.

AU - Bloomfield, C. D.

AU - Nicolet, D.

AU - Assi, S. A.

AU - Ptasinska, A.

AU - Heidenreich, O.

AU - Bonifer, C.

AU - Kitamura, T.

AU - Nassar, N. N.

AU - Mulloy, J. C.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

AB - The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

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DO - 10.1038/leu.2015.275

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JO - Leukemia

JF - Leukemia

IS - 3

ER -

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

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