Figure 5
Figure 5. FGF2 is increased in the bone marrow of patients without KD mutations and decreases with ponatinib treatment. Bone marrow core biopsies obtained from normal controls (surgical joint replacement patients), CML patients at diagnosis, tyrosine kinase inhibitor resistant patients before ponatinib therapy (pre-ponatinib), and responsive patients post-ponatinib were collected and evaluated for FGF2 by IHC as described in “Methods.” Representative images of (A) normal control, (B) pre-ponatinib marrow of a patient without KD mutation, and (C) the same patient post-ponatinib. FGF2 is normally expressed in marrow stroma (A); arrows indicate nonstromal areas of increased FGF2 in resistant patients (B). (D) IHC images from normal controls, patients at diagnosis, and pre-ponatinib patients who responded to ponatinib (with and without KD mutations) were analyzed with Aperio ImageScope software to quantify FGF2 staining. The line indicates the median value. Statistically significant differences were evaluated using a 2-tailed Student t test. (E) Paired IHC analysis of pre- and post-ponatinib bone marrow of patients treated with ponatinib (same as D). Patients without KD mutations had an average decrease of 15.9% in FGF2 staining, whereas patients with KD mutations were more variable. The differences pre- and post-ponatinib were analyzed by the 2-tailed Student t test for significance. A single patient without KD mutations who failed IM, DAS, NIL, and ponatinib is plotted with a dotted line for comparison (see Table 1). (F) CD34+ cells from newly diagnosed CML patients were resuspended in methocult H4534 ± FGF2 10 ng/mL and ± 5 μM IM. Cells were plated in triplicate, cultured for 14 days, and then CFU-GM colonies were counted. The data are presented as the percent of untreated control (control or FGF2). The differences between control and FGF2 were analyzed by 2-tailed Student t test for significance. *P < .05. (G) Model of FGF2 paracrine protection of CML cells based upon data in this article and previous publications regarding FGF2 autocrine/paracrine stromal cell signaling.44,45

FGF2 is increased in the bone marrow of patients without KD mutations and decreases with ponatinib treatment. Bone marrow core biopsies obtained from normal controls (surgical joint replacement patients), CML patients at diagnosis, tyrosine kinase inhibitor resistant patients before ponatinib therapy (pre-ponatinib), and responsive patients post-ponatinib were collected and evaluated for FGF2 by IHC as described in “Methods.” Representative images of (A) normal control, (B) pre-ponatinib marrow of a patient without KD mutation, and (C) the same patient post-ponatinib. FGF2 is normally expressed in marrow stroma (A); arrows indicate nonstromal areas of increased FGF2 in resistant patients (B). (D) IHC images from normal controls, patients at diagnosis, and pre-ponatinib patients who responded to ponatinib (with and without KD mutations) were analyzed with Aperio ImageScope software to quantify FGF2 staining. The line indicates the median value. Statistically significant differences were evaluated using a 2-tailed Student t test. (E) Paired IHC analysis of pre- and post-ponatinib bone marrow of patients treated with ponatinib (same as D). Patients without KD mutations had an average decrease of 15.9% in FGF2 staining, whereas patients with KD mutations were more variable. The differences pre- and post-ponatinib were analyzed by the 2-tailed Student t test for significance. A single patient without KD mutations who failed IM, DAS, NIL, and ponatinib is plotted with a dotted line for comparison (see Table 1). (F) CD34+ cells from newly diagnosed CML patients were resuspended in methocult H4534 ± FGF2 10 ng/mL and ± 5 μM IM. Cells were plated in triplicate, cultured for 14 days, and then CFU-GM colonies were counted. The data are presented as the percent of untreated control (control or FGF2). The differences between control and FGF2 were analyzed by 2-tailed Student t test for significance. *P < .05. (G) Model of FGF2 paracrine protection of CML cells based upon data in this article and previous publications regarding FGF2 autocrine/paracrine stromal cell signaling.44,45 

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