Abstract
BackgroundAs one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38−CD58− fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies.MethodsRNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT-PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR–ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti-CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice.ResultsRNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level.ConclusionsIn summary, this pre-clinical study provides a scientific rationale for simultaneously targeting BCR–ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL.
Highlights
As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs)
Using an anti-CD122-conditioned non-obese diabetic/ severe combined immunodeficiency (NOD/SCID) xenograft mouse assay, we previously reported that LPCs were enriched in the CD34+CD38−CD58− fraction in human Ph+ALL [10]
JAK2 mRNA and phospho‐JAK2 were more highly expressed in the LPCs fraction than in the other cell fractions in patients with de novo Ph+ALL A Venn diagram shows that 3722 genes were differentially expressed between the LPC1 and Other Cell1 fractions sorted from patient No 1 with de novo P h+ALL, whereas 4162 genes were differentially expressed between the LPC2 and Other Cell2 fractions from patient No 2, and 2800 differentially expressed genes were co-expressed in both patients (Fig. 2a)
Summary
As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). A cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, highlighting the need for novel LPCsbased therapeutic strategies. High-dose chemotherapy, TKIs, and even lethal conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) kill leukemia cells but cannot effectively eliminate LPCs. Using an anti-CD122-conditioned non-obese diabetic/ severe combined immunodeficiency (NOD/SCID) xenograft mouse assay, we previously reported that LPCs were enriched in the CD34+CD38−CD58− fraction in human Ph+ALL [10]. A cohort study demonstrated that Ph+ALL patients with LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than did the group with other cell phenotypes, even when receiving uniform front-line imatinib-based therapy pre- and post-allotransplant [18]. It is imperative to identify novel therapeutic targets based on LPCs to improve the prognosis of Ph+ALL patients
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