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Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients.

Advani AS, Gibson SE, Douglas E, Jin T, Zhao X, Kalaycio M, Copelan E, Sobecks R, Sekeres M, Sungren S, Hsi ED - BMC Cancer (2010)

Bottom Line: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09).This association remained statistically significant in multivariate analysis.These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, The Cleveland Clinic, Cleveland, OH, USA. advania@ccf.org

ABSTRACT

Background: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS).

Methods: Patients > or = 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis.

Results: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis.

Conclusions: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.

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Related in: MedlinePlus

Histone H4 Acetylation in ALL Patient Samples. A patient with high levels of histone acetylation (Acetyl-histone H4, original magnification × 400). Olympus BX50 microscope, 100×/1.25 Olympus oil objective, Olympus DP71 camera.
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Figure 6: Histone H4 Acetylation in ALL Patient Samples. A patient with high levels of histone acetylation (Acetyl-histone H4, original magnification × 400). Olympus BX50 microscope, 100×/1.25 Olympus oil objective, Olympus DP71 camera.

Mentions: Forty-six patients with ALL treated during this time period had evaluable bone marrow core biopsies. Patient characteristics are described in (Table 1). The median age was 36 years (range 18-66). The median white blood count was 7800/μL (range 840-278,000) and median LDH 763 U/L (range 123-4608). 19 patients (41%) had poor risk cytogenetics, 11 patients (24% ) normal karyotype, 9 patients (20%) miscellaneous abnormalities, and 7 patients (15%) unknown cytogenetics as defined by CALGB criteria. Forty-two patients (91%) had precursor B-cell ALL, 3 patients (7%) T-cell ALL, and 1 patient (2%) mixed lineage leukemia. Thirty-four patients (74%) had strong nuclear expression of acetylated histone H4. Of the T-cell ALL patients, 2 out of 3 patients (67%) had strong nuclear expression of acetylated histone H4. (Figures 5 and 6) illustrate a patient with weak nuclear expression of acetylated histone H4 (Figure 5) and a patient with strong nuclear expression of acetylated histone H4 (Figure 6). There were no associations of age, white blood count at diagnosis, or cytogenetics with histone acetylation.


Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients.

Advani AS, Gibson SE, Douglas E, Jin T, Zhao X, Kalaycio M, Copelan E, Sobecks R, Sekeres M, Sungren S, Hsi ED - BMC Cancer (2010)

Histone H4 Acetylation in ALL Patient Samples. A patient with high levels of histone acetylation (Acetyl-histone H4, original magnification × 400). Olympus BX50 microscope, 100×/1.25 Olympus oil objective, Olympus DP71 camera.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2921396&req=5

Figure 6: Histone H4 Acetylation in ALL Patient Samples. A patient with high levels of histone acetylation (Acetyl-histone H4, original magnification × 400). Olympus BX50 microscope, 100×/1.25 Olympus oil objective, Olympus DP71 camera.
Mentions: Forty-six patients with ALL treated during this time period had evaluable bone marrow core biopsies. Patient characteristics are described in (Table 1). The median age was 36 years (range 18-66). The median white blood count was 7800/μL (range 840-278,000) and median LDH 763 U/L (range 123-4608). 19 patients (41%) had poor risk cytogenetics, 11 patients (24% ) normal karyotype, 9 patients (20%) miscellaneous abnormalities, and 7 patients (15%) unknown cytogenetics as defined by CALGB criteria. Forty-two patients (91%) had precursor B-cell ALL, 3 patients (7%) T-cell ALL, and 1 patient (2%) mixed lineage leukemia. Thirty-four patients (74%) had strong nuclear expression of acetylated histone H4. Of the T-cell ALL patients, 2 out of 3 patients (67%) had strong nuclear expression of acetylated histone H4. (Figures 5 and 6) illustrate a patient with weak nuclear expression of acetylated histone H4 (Figure 5) and a patient with strong nuclear expression of acetylated histone H4 (Figure 6). There were no associations of age, white blood count at diagnosis, or cytogenetics with histone acetylation.

Bottom Line: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09).This association remained statistically significant in multivariate analysis.These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, The Cleveland Clinic, Cleveland, OH, USA. advania@ccf.org

ABSTRACT

Background: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS).

Methods: Patients > or = 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis.

Results: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis.

Conclusions: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.

Show MeSH
Related in: MedlinePlus