JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia

Charlotte EJ Downes; Barbara J McClure; John B Bruning; Susan L Heatley; Chung H. Kok; Timothy P. Hughes; David T Yeung; Deborah L White

JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia

Charlotte EJ Downes
, Barbara J McClure
, John B Bruning
, Susan L Heatley
, Chung H. Kok
, Timothy P. Hughes
, David T Yeung
, Deborah L White

Research output: Contribution to conference › Poster

Abstract

Janus kinase 2 (JAK2) rearrangements (JAK2r) occur in approximately 5% of paediatric B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with poor prognosis. The resultant gene fusions drive leukaemogenesis through constitutive kinase activation, which may be amenable to JAK inhibitor therapy. Type-I JAK inhibitors bind in the ATP-binding site of JAK2 in the active conformation, while type-II JAK inhibitors bind in the ATP-binding site and in an allosteric site of JAK2 in the inactive conformation. A clinical trial is currently assessing the type-I JAK1/2 inhibitor, ruxolitinib (rux) in high-risk B-ALL cases harbouring JAK2 pathway alterations. Given the development of treatment resistance to targeted inhibitors in other diseases, elucidating mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance.

Original language	English
Number of pages	1
Publication status	Published - 2019
Externally published	Yes
Event	Australian Society for Medical Research South Australian Scientific Meeting 2019: Public, Political, Scientific Advocacy - Adelaide, Australia Duration: 5 Jun 2019 → …

Conference

Conference	Australian Society for Medical Research South Australian Scientific Meeting 2019
Abbreviated title	ASMR SA Annual Scientific Meeting 2019
Country/Territory	Australia
City	Adelaide
Period	5/06/19 → …

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Lymphoblastic Leukaemia
JAK2
Inhibitors

Precision medicine approaches for JAK2-rearranged ALL: The efficacy of targeted therapies and molecular mechanisms of drug resistance
Toomes, C. (Associate Investigator), White, D. L. (Chief Investigator (Project Lead)), McClure, B. (Associate Investigator) & Bruning, J. B. (Associate Investigator)
12/03/18 → 31/12/22
Project: Research

Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia
Downes, C. E. J., McClure, B. J., Bruning, J. B., Page, E., Breen, J., Rehn, J., Yeung, D. T. & White, D. L., 10 Aug 2021, In: npj Precision Oncology. 5, 13 p., 75.
Research output: Contribution to journal › Article › peer-review

Open Access
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21 Citations (Scopus)

62 Downloads (Pure)

Cite this

Downes, C. EJ., McClure, B. J., Bruning, J. B., Heatley, S. L., Kok, C. H., Hughes, T. P., Yeung, D. T., & White, D. L. (2019). JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia. Poster session presented at Australian Society for Medical Research South Australian Scientific Meeting 2019, Adelaide, South Australia, Australia.

@conference{591be5782c6d48b090125cb8974e677a,

title = "JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia",

abstract = "Janus kinase 2 (JAK2) rearrangements (JAK2r) occur in approximately 5\% of paediatric B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with poor prognosis. The resultant gene fusions drive leukaemogenesis through constitutive kinase activation, which may be amenable to JAK inhibitor therapy. Type-I JAK inhibitors bind in the ATP-binding site of JAK2 in the active conformation, while type-II JAK inhibitors bind in the ATP-binding site and in an allosteric site of JAK2 in the inactive conformation. A clinical trial is currently assessing the type-I JAK1/2 inhibitor, ruxolitinib (rux) in high-risk B-ALL cases harbouring JAK2 pathway alterations. Given the development of treatment resistance to targeted inhibitors in other diseases, elucidating mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. ",

keywords = "Lymphoblastic Leukaemia, JAK2, Inhibitors",

author = "Downes, \{Charlotte EJ\} and McClure, \{Barbara J\} and Bruning, \{John B\} and Heatley, \{Susan L\} and Kok, \{Chung H.\} and Hughes, \{Timothy P.\} and Yeung, \{David T\} and White, \{Deborah L\}",

year = "2019",

language = "English",

note = "Australian Society for Medical Research South Australian Scientific Meeting 2019 : Public, Political, Scientific Advocacy, ASMR SA Annual Scientific Meeting 2019 ; Conference date: 05-06-2019",

}

JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia. / Downes, Charlotte EJ; McClure, Barbara J; Bruning, John B et al.
2019. Poster session presented at Australian Society for Medical Research South Australian Scientific Meeting 2019, Adelaide, South Australia, Australia.

Research output: Contribution to conference › Poster

TY - CONF

T1 - JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia

AU - Downes, Charlotte EJ

AU - McClure, Barbara J

AU - Bruning, John B

AU - Heatley, Susan L

AU - Kok, Chung H.

AU - Hughes, Timothy P.

AU - Yeung, David T

AU - White, Deborah L

PY - 2019

Y1 - 2019

N2 - Janus kinase 2 (JAK2) rearrangements (JAK2r) occur in approximately 5% of paediatric B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with poor prognosis. The resultant gene fusions drive leukaemogenesis through constitutive kinase activation, which may be amenable to JAK inhibitor therapy. Type-I JAK inhibitors bind in the ATP-binding site of JAK2 in the active conformation, while type-II JAK inhibitors bind in the ATP-binding site and in an allosteric site of JAK2 in the inactive conformation. A clinical trial is currently assessing the type-I JAK1/2 inhibitor, ruxolitinib (rux) in high-risk B-ALL cases harbouring JAK2 pathway alterations. Given the development of treatment resistance to targeted inhibitors in other diseases, elucidating mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance.

AB - Janus kinase 2 (JAK2) rearrangements (JAK2r) occur in approximately 5% of paediatric B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with poor prognosis. The resultant gene fusions drive leukaemogenesis through constitutive kinase activation, which may be amenable to JAK inhibitor therapy. Type-I JAK inhibitors bind in the ATP-binding site of JAK2 in the active conformation, while type-II JAK inhibitors bind in the ATP-binding site and in an allosteric site of JAK2 in the inactive conformation. A clinical trial is currently assessing the type-I JAK1/2 inhibitor, ruxolitinib (rux) in high-risk B-ALL cases harbouring JAK2 pathway alterations. Given the development of treatment resistance to targeted inhibitors in other diseases, elucidating mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance.

KW - Lymphoblastic Leukaemia

KW - JAK2

KW - Inhibitors

M3 - Poster

T2 - Australian Society for Medical Research South Australian Scientific Meeting 2019

Y2 - 5 June 2019

ER -

JAK2 kinase domain mutations confer resistance to JAK inhibitors in a pro-B cell model of a high-risk acute lymphoblastic leukaemia

Abstract

Conference

UN SDGs

Keywords

Fingerprint

Projects

Precision medicine approaches for JAK2-rearranged ALL: The efficacy of targeted therapies and molecular mechanisms of drug resistance

Research output

Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia

Cite this