Biomarker Predicts Worse Outcome in Chronic Myeloid Leukemia

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.