Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression

P.A. Beer, D.J.H.F. Knapp, P.H. Miller, N. Kannan, I. Sloma, Kathy Heel, S. Babovic, E. Bulaeva, G. Rabu, J. Terry, B.J. Druker, M.M. Loriaux, K.R. Loeb, J.P. Radich, Wendy Erber, C.J. Eaves

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Abstract

© 2015 by The American Society of Hematology. Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoformof IKAROS (IK6) in CP-CML patients' CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils.Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.
Original languageEnglish
Pages (from-to)504-515
JournalBlood
Volume125
Issue number3
DOIs
Publication statusPublished - 2015

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Leukemia, Myeloid, Chronic Phase
Emitter coupled logic circuits
Myeloid Cells
Blast Crisis
Disease Progression
STAT5 Transcription Factor
Basophils
Acute Myeloid Leukemia
Bone
Leukemia
Bone Marrow
Chemical activation
Display devices
Proteins
Therapeutics

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Beer, P. A., Knapp, D. J. H. F., Miller, P. H., Kannan, N., Sloma, I., Heel, K., ... Eaves, C. J. (2015). Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression. Blood, 125(3), 504-515. https://doi.org/10.1182/blood-2014-06-581173
Beer, P.A. ; Knapp, D.J.H.F. ; Miller, P.H. ; Kannan, N. ; Sloma, I. ; Heel, Kathy ; Babovic, S. ; Bulaeva, E. ; Rabu, G. ; Terry, J. ; Druker, B.J. ; Loriaux, M.M. ; Loeb, K.R. ; Radich, J.P. ; Erber, Wendy ; Eaves, C.J. / Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression. In: Blood. 2015 ; Vol. 125, No. 3. pp. 504-515.
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abstract = "{\circledC} 2015 by The American Society of Hematology. Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoformof IKAROS (IK6) in CP-CML patients' CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils.Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.",
author = "P.A. Beer and D.J.H.F. Knapp and P.H. Miller and N. Kannan and I. Sloma and Kathy Heel and S. Babovic and E. Bulaeva and G. Rabu and J. Terry and B.J. Druker and M.M. Loriaux and K.R. Loeb and J.P. Radich and Wendy Erber and C.J. Eaves",
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Beer, PA, Knapp, DJHF, Miller, PH, Kannan, N, Sloma, I, Heel, K, Babovic, S, Bulaeva, E, Rabu, G, Terry, J, Druker, BJ, Loriaux, MM, Loeb, KR, Radich, JP, Erber, W & Eaves, CJ 2015, 'Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression' Blood, vol. 125, no. 3, pp. 504-515. https://doi.org/10.1182/blood-2014-06-581173

Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression. / Beer, P.A.; Knapp, D.J.H.F.; Miller, P.H.; Kannan, N.; Sloma, I.; Heel, Kathy; Babovic, S.; Bulaeva, E.; Rabu, G.; Terry, J.; Druker, B.J.; Loriaux, M.M.; Loeb, K.R.; Radich, J.P.; Erber, Wendy; Eaves, C.J.

In: Blood, Vol. 125, No. 3, 2015, p. 504-515.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression

AU - Beer, P.A.

AU - Knapp, D.J.H.F.

AU - Miller, P.H.

AU - Kannan, N.

AU - Sloma, I.

AU - Heel, Kathy

AU - Babovic, S.

AU - Bulaeva, E.

AU - Rabu, G.

AU - Terry, J.

AU - Druker, B.J.

AU - Loriaux, M.M.

AU - Loeb, K.R.

AU - Radich, J.P.

AU - Erber, Wendy

AU - Eaves, C.J.

PY - 2015

Y1 - 2015

N2 - © 2015 by The American Society of Hematology. Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoformof IKAROS (IK6) in CP-CML patients' CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils.Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.

AB - © 2015 by The American Society of Hematology. Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoformof IKAROS (IK6) in CP-CML patients' CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils.Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.

U2 - 10.1182/blood-2014-06-581173

DO - 10.1182/blood-2014-06-581173

M3 - Article

VL - 125

SP - 504

EP - 515

JO - Blood

JF - Blood

SN - 0006-4971

IS - 3

ER -