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Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

Xu N, Li YL, Li X, Zhou X, Cao R, Li H, Li L, Lu ZY, Huang JX, Fan ZP, Huang F, Zhou HS, Zhang S, Liu Z, Zhu HQ, Liu QF, Liu XL - J Hematol Oncol (2016)

Bottom Line: Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs).However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001).In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

ABSTRACT

Background: Frequency relapses are common in Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) following tyrosine kinase inhibitors (TKIs). CDKN2A/B is believed to contribute to this chemotherapy resistance.

Methods: To further investigate the association between CDKN2 status and TKI resistance, the prevalence of CDKN2 deletions and its correlation with a variety of clinical features was assessed in 135 Ph-positive ALL patients using interphase fluorescence in situ hybridization (I-FISH).

Results: Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001). Moreover, deletions of CDKN2 resulted in lower rates of complete molecular response (undetectable BCR/ABL), increased cumulative incidence of relapse, short overall survival (OS), and disease-free survival (DFS) time (P < 0.05) even though these patients received chemotherapy plus TKIs followed by allogenic hematopoietic stem cell transplantation (Allo-HSCT). In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.

Conclusions: CDKN2 deletion is frequently acquired during Ph-positive ALL progression and serves as a poor prognostic marker of long-term outcome in Ph-positive ALL patients with CDKN2 deletion even after the second-generation tyrosine kinase inhibitor treatment.

No MeSH data available.


Related in: MedlinePlus

Representative of fluorescence images in situ hybridization. a Normal cells presented with double green and red signals; b hemizygous cells presented with loss of one red signal; c homozygous cells presented with a loss of both red signals (p16) and only retained with two green signals (chromosome 9); dred and green signal fusion (BCR/ABL+)
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Fig1: Representative of fluorescence images in situ hybridization. a Normal cells presented with double green and red signals; b hemizygous cells presented with loss of one red signal; c homozygous cells presented with a loss of both red signals (p16) and only retained with two green signals (chromosome 9); dred and green signal fusion (BCR/ABL+)

Mentions: We included CDKN2A (encoding p16 and p14) and CDKN2B (encoding p15), the two subunits of CDKN2, in our current study. The deletion of CDKN2 was defined as the loss of CDKN2A or CDKN2B which contained both hemizygous deletion and homozygous deletion genotypes. Interphase fluorescence in situ hybridization (I-FISH) experiments were performed with commercial kits (Cat No. LH009, Cytocell, Cambridge, UK) including two red-labeled CDKN2 probe kits, one red-labeled BCR and one green-labeled and ABL probe kit according to the manufacturers’ protocols (Fig. 1). Bone marrow cells of all patients were collected for detection of CDKN2 (covers a 193-kD region of 9q21.3, extending from 105 kD telomeric of p16 gene to 46 kD centromeric of CDKN2B) and BCR/ABL. We analyzed interphase cells according to the manufacturer’s instructions and the ISCN (2005) criteria [7].Fig. 1


Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

Xu N, Li YL, Li X, Zhou X, Cao R, Li H, Li L, Lu ZY, Huang JX, Fan ZP, Huang F, Zhou HS, Zhang S, Liu Z, Zhu HQ, Liu QF, Liu XL - J Hematol Oncol (2016)

Representative of fluorescence images in situ hybridization. a Normal cells presented with double green and red signals; b hemizygous cells presented with loss of one red signal; c homozygous cells presented with a loss of both red signals (p16) and only retained with two green signals (chromosome 9); dred and green signal fusion (BCR/ABL+)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4836197&req=5

Fig1: Representative of fluorescence images in situ hybridization. a Normal cells presented with double green and red signals; b hemizygous cells presented with loss of one red signal; c homozygous cells presented with a loss of both red signals (p16) and only retained with two green signals (chromosome 9); dred and green signal fusion (BCR/ABL+)
Mentions: We included CDKN2A (encoding p16 and p14) and CDKN2B (encoding p15), the two subunits of CDKN2, in our current study. The deletion of CDKN2 was defined as the loss of CDKN2A or CDKN2B which contained both hemizygous deletion and homozygous deletion genotypes. Interphase fluorescence in situ hybridization (I-FISH) experiments were performed with commercial kits (Cat No. LH009, Cytocell, Cambridge, UK) including two red-labeled CDKN2 probe kits, one red-labeled BCR and one green-labeled and ABL probe kit according to the manufacturers’ protocols (Fig. 1). Bone marrow cells of all patients were collected for detection of CDKN2 (covers a 193-kD region of 9q21.3, extending from 105 kD telomeric of p16 gene to 46 kD centromeric of CDKN2B) and BCR/ABL. We analyzed interphase cells according to the manufacturer’s instructions and the ISCN (2005) criteria [7].Fig. 1

Bottom Line: Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs).However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001).In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

ABSTRACT

Background: Frequency relapses are common in Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) following tyrosine kinase inhibitors (TKIs). CDKN2A/B is believed to contribute to this chemotherapy resistance.

Methods: To further investigate the association between CDKN2 status and TKI resistance, the prevalence of CDKN2 deletions and its correlation with a variety of clinical features was assessed in 135 Ph-positive ALL patients using interphase fluorescence in situ hybridization (I-FISH).

Results: Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001). Moreover, deletions of CDKN2 resulted in lower rates of complete molecular response (undetectable BCR/ABL), increased cumulative incidence of relapse, short overall survival (OS), and disease-free survival (DFS) time (P < 0.05) even though these patients received chemotherapy plus TKIs followed by allogenic hematopoietic stem cell transplantation (Allo-HSCT). In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups.

Conclusions: CDKN2 deletion is frequently acquired during Ph-positive ALL progression and serves as a poor prognostic marker of long-term outcome in Ph-positive ALL patients with CDKN2 deletion even after the second-generation tyrosine kinase inhibitor treatment.

No MeSH data available.


Related in: MedlinePlus