Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor

Naftaly Meydan, Tom Grunberger, Harjit Dadi, Michal Shahar, Enrico Arpaia, Zvi Lapidot, J. Steven Leeder, Melvin Freedman, Amos Cohen, Aviv Gazit, Alexander Levitzki, Chaim M. Roifman

Research output: Contribution to journalArticlepeer-review

847 Scopus citations

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemo therapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor tells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

Original languageEnglish
Pages (from-to)645-648
Number of pages4
JournalNature
Volume379
Issue number6566
DOIs
StatePublished - 15 Feb 1996
Externally publishedYes

ASJC Scopus subject areas

  • General

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