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. 2014 Sep;28(9):1918-22.
doi: 10.1038/leu.2014.152. Epub 2014 May 5.

Acceleration of Bcr-Abl+ leukemia induced by deletion of JAK2

E Grundschober  1 , A Hoelbl-Kovacic  1 , N Bhagwat  2 , B Kovacic  3 , R Scheicher  1 , E Eckelhart  4 , K Kollmann  1 , M Keller  5 , F Grebien  6 , K U Wagner  7 , R L Levine  8 , V Sexl  1
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Free PMC article

Acceleration of Bcr-Abl+ leukemia induced by deletion of JAK2

E Grundschober et al. Leukemia. 2014 Sep.
Free PMC article
No abstract available

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Figures

Figure 1
Figure 1
Jak2 deletion accelerates BCR-ABLp210+ leukemia in mice but leads to a reduction of LSKs in normal hematopoiesis. Jak2Δ/Δ and Jak2f/fMxCre+ BM cells (1 × 106) were injected in non-irradiated NSG mice (n=12) (a) Mice that received Jak2Δ/Δ BCR-ABLp210-transformed BM succumb prematurely to leukemia. Short lines indicate individual mice that were killed as control. Mice of the Jak2Δ/Δ cohort display (b) increased peripheral WBCs and (c) spleen weights. (d) Percentages of BCR-ABLp210+/GFP+ cells are increased in BMs of mice that received Jak2Δ/Δ BCR-ABLp210-transformed BM compared with control animals. (e) Jak2Δ/Δ BCR-ABLp210+/GFP+ cells contribute to B-cell and erythroid lineages. (f) Increased percentages of BCR-ABLp210+/GFP+ LSKs in mice that received a Jak2Δ/Δ transplant. (g) Supplementation of Jak2Δ/Δ BM with HSC-depleted carrier BM leads to premature death. Non-transformed Jak2Δ/Δ BM was mixed with high-purity sorted HSC-depleted C57BL/6 J BM cells and injected into lethally irradiated recipients (n=8). Scheme depicts experimental setup. (h) Numbers of LSKs are severely reduced in mice that received a mixture of Jak2Δ/Δ BM and HSC-depleted carrier cells. Hematocrit (HCT) levels remained unaltered upon JAK2 loss. (i) Dose-response curves of BCR-ABLp210+ LSKs incubated for 24 h in the presence of ruxolitinib (300 nM) and increasing doses of imatinib (ranging from 10 nM to 2 μM). (j) Frequencies of apoptotic (Annexin V+) LSKs upon imatinib treatment (48 h incubation; 2 μM). Asterisks denote level of statistical significance as determined by an unpaired t-test: *P⩽0.05; **P⩽0.01; ***P⩽0.001.
Figure 2
Figure 2
Jak2-deficient BM harbors reduced numbers of HSCs and shows a selective disadvantage in competitive transplantations. Jak2f/fMxCre+ and wtMx1Cre+ mice were treated with poly(I:C) every 3 days for 2 weeks to induce gene deletion (a–c; n=8 for each genotype). (a) Loss of HSCs upon Jak2 deletion. Representative fluorescence-activated cell sorting (FACS) plots indicate reduction of HSC numbers upon Jak2 deletion. After 2 weeks, BM of Jak2Δ/Δ cells displayed significantly reduced numbers of LSK and fraction A, B and C cells. Upper panels: Representative FACS plot depicting LSK cells that were further subdivided by CD150 and CD48 expression. Percentages of cells belonging to fraction A, B or C are provided next to the plot. (b) Summary of LSK numbers in Jak2Δ/Δ and wtMx1Cre+ mice. BM cells were analyzed as described in (a). (c) Higher numbers of HSCs in G0 phase in Jak2Δ/Δ mice. BM cells of Jak2Δ/Δ and wtMx1Cre+ mice were analyzed for Ki67 and 4′,6-diamidino-2-phenylindole incorporation. The majority of Jak2Δ/Δ cells underwent the G0 phase of the cell cycle. (d) Analyses of peripheral blood (PB) of poly(I:C)-treated wtMx1Cre+ and Jak2Δ/Δ mice. Hematocrit (HCT), RBCs and PLT counts as well as percentages of lymphocytes and granulocytes are summarized in bar graphs. (e) BM of Ly5.1+ mice was mixed with either Jak2f/fMxCre+ or wtMx1Cre (both Ly5.2+) BM cells and injected intravenously into lethally irradiated Ly5.1+ mice. Post transplantation, mice received poly (I:C) to delete Jak2. Upper panels: percentages of peripheral blood cells expressing Ly5.1 or Ly5.2 of mice that received a Ly5.1/wtMx1Cre (left panel) or a Ly5.1/Jak2f/fMxCre+ (right panel) mixture of cells (n=9 each). Lower panels: percentages of CD11b+Gr-1+Ly.5.2+ (left panel) and B220+Ly5.2+ (right panel) cells in the peripheral blood of mice that received a Ly5.1/wt or a Ly5.1/Jak2f/fMxCre+ mixture of cells are shown. (f) Numbers of Jak2Δ/Δ HSCs and MPs are markedly reduced in a competitive setting with wt cells. Asterisks denote level of statistical significance as determined by an unpaired t-test: *P⩽0.05; **P⩽0.01; ****P⩽0.0001.
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