93. Evidence of BCR::ABL1 fusion ‘seed’ many years before CML disease presentation

Aly Abdelkareem

Ramakrishnan Sasi


Ramakrishnan Sasi, PhD., FABMGG, FACMGG.

Current Position: Medical Director, Cytogenetics and Microarray testing Labs, Assistant Professor, Department of Pathology, West Virginia University, Morgantown, WV. 

Previous position: Adjunct Professor in the Department of Clinical Sciences, Northern Michigan University; Medical Director of Cytogenetics and Molecular Pathology Lab, Marquette General Health System; Medical Staff, William Beaumont Hospital.

Degree:  Ph.D., Molecular Genetics, Indian Institute of Science Bangalore, India, 1980.

Fellowship training:  ABMG fellowship training in Clinical Cytogenetics, Cincinnati Children’s Hospital, Cincinnati, OH (Dr. Gregory Grabowksi), ABMG fellowship training in Clinical Molecular Genetics, McGill University, Montreal (Dr. David Rosenblatt) 1994 – 1996; Alberta Heritage Post Doctoral Fellow in Molecular Genetics, University of Calgary, Alberta (Dr. Kostas Iatrou) 2004 – 2006; Post doctoral fellow in Biochemistry, Brandeis University, Waltham, MA (Dr. Gerald Fasman) 1980 – 1983

Prior Experience:  Assistant Medical Director, Sonora Quest Laboratories, Tempe, AZ, 2004-2005; Director, Cancer Genetics Inc., Cambridge, MA, 2003 – 2004; Scientific Director in Cytogenetics, Genetic Associates Inc., Nashville, TN, 2002 – 2003; Scientist, Fraser Laboratories, Royal Victoria Hospital, McGill University, Montreal, 1996-1999; Ph.D. Laboratory Scientist(III) / Clinical Lecturer, University of Alberta Hospital, Edmonton, Alberta (1986-1994).

Board Certifications:  Diplomate of ABMGG in Clinical Molecular Genetics and Clinical Cytogenetics from 1996 – present, Fellow of American College of Medical Genetics, 2003 –  Present; New York State Department of Health, Laboratory Director Certification in Cytogenetics and Genetic testing, 2001 –  Present; Tennessee State Department of Health Medical Laboratory Personal License Certification as Director in Clinical Cytogenetics and Clinical Molecular Genetics, 2002 – Present.


Ramakrishnan Sasia, Michelle Spruillb, Peter L. Perrottaa

aWest Virginia University, Morgantown, WV, United States; bWest Virginia University Medicine, Morgantown, WV, United States

Key mutations that drive the initiation of cancer can arrive decades before the clinical manifestation of the disease. In CML, BCR::ABL1 fusion can occur many years before diagnosis.

A patient was referred for suspicion of CML. Both karyotype and FISH analysis identified the t(9;22)(q22;q12) in 98.5% of cells analyzed. The patient responded to imatinib and achieved a complete cytogenetic response.

Clinical history revealed that this patient had presented with cytopenia six years before and was evaluated for MDS. Cytogenetic analysis at that time revealed del(20q) as the sole abnormality. No treatment was given since the presence of isolated del(20q) is not considered evidence of MDS in the absence of diagnostic morphologic criteria. Analysis of archived bone marrow pellets from this previous specimen revealed the presence of BCR::ABL1 in 1.8% of cells.

The seed and soil hypothesis proposes that the genetic alteration that leads to the formation of the BCR::ABL1 fusion gene (the ‘seed’) may occur many years before the onset of symptoms. The ‘soil’ refers to the microenvironment in the bone marrow where the leukemic stem cells reside. The environmental conditions required for the manifestation of CML are not fully understood, but it is thought to involve several factors including mutations and epigenetic changes.

This case reaffirms the seed and soil hypothesis can be applied to CML and demonstrates precancerous evolution by detecting key mutations in the stem cell microenvironment years before diagnosis. Further understanding could lead to early detection and treatment for patients at risk for developing hematological malignancies.