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Identification of factors associated with development and progression of monoclonal B-cell lymphocytosis (MBL)

Principal Investigator
Name
Ola Landgren
Degrees
MD, PhD
Institution
Sylvester Comprehensive Cancer Center, University of Miami
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2009-0561
Initial CDAS Request Approval
Jan 21, 2010
Title
Identification of factors associated with development and progression of monoclonal B-cell lymphocytosis (MBL)
Summary
Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies accounting for ~11% of all hematologic neoplasms. CLL remains an incurable and devastating malignancy. In addition to having a life expectancy that is substantially shorter than agematched individuals in the general population, the 100,000 individuals in the United States living with CLL must also deal with an increased risk of infections, 2nd cancers, and autoimmune complications that can have profound consequences on quality of life. While there have been remarkable advances in our understanding of CLL, we are now poised for even more dramatic breakthroughs due to the recent discovery of the precursor state to CLL, monoclonal B-cell lymphocytosis (MBL). Individuals with MBL have a clonal B-cell population present in the peripheral blood, an absolute B-cell count <5x109/L and no other features of a lymphoproliferative disorder. Prevalence studies in Great Britain and Italy suggest that 3-5% of the general population over the age of 40 has MBL indicating that MBL may be one of the most common premalignant conditions in humans and that the precursor state that is 200-300 times more common than the disease itself. We and others recently determined that ~1% of individuals with MBL per year will progress to symptomatic CLL requiring treatment. Understanding the factors that place individuals at risk for MBL and identifying the molecular/biologic events that lead some individuals with MBL to progress to CLL would enable us to develop and test future interventions that prevent or delay progression of MBL to CLL. Building from our extensive research in CLL and MBL, we believe the two crucial questions that must now be addressed are to identify 1) what genetic and behavioral risk factors lead to the development of MBL? and 2) what genetic and biologic events cause some individuals with MBL to progress while the majority remain stable. We will address these questions through the studies detailed in the current proposal.
Aims

Aim 1: Identify risk factors associated with developing MBL.
Hypothesis: A combination of genetic, environmental, and behavioral factors predispose individuals to developing MBL. With respect to genetic factors, we hypothesize the risk of MBL is associated with the same 6 common, low-penetrance, germline susceptibility loci known to be associated with CLL (i.e. these loci relate to the risk of developing the precursor state in addition to the risk of developing the disease). We also hypothesize that the greater incidence of CLL among whites is due to a higher prevalence of the precursor lesion MBL rather than differences in the rate of progression of MBL to CLL by race/ethnicity. Finally, based on our findings in CLL (see preliminary results), we also anticipate specific modifiable dietary factors contribute to the risk of developing MBL.
Aim 2: Identify biologic and genetic defects associated with progression of MBL to CLL.
Hypothesis: Once initiated, the risk of progression of MBL to CLL is related to specific biologic (IGHV mutation, Zap-70, CD49d, CD38, paraprotein production) and genetic characteristics of the clonal B-cell as well as biologic characteristics (innate immune system) of the host. A nested case control study will be conducted to evaluate these aspects in the PLCO.

Collaborators

Susan Slager (Mayo Clinic)
Rafael Fonseca (Mayo Clinic)
Curtis Hanson (Mayo Clinic)
Vincent Rajkumar (Mayo Clinic)
Ola Landgren (Sylvester Comprehensive Cancer Center, University of Miami)
Neil Kay (Mayo Clinic)
Tait Shanafelt (Mayo Clinic)
Neil Caporaso (NCI, DCEG)

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