A 51-year-old woman was diagnosed with essential thrombocythemia (ET) in 1995, presenting with a markedly elevated platelet count of 1240 × 10⁹/L and hypercellular bone marrow dominated by large, mature megakaryocytes. Over the next 16 years, she remained stable on anti-thrombotic therapy, with no evidence of thrombosis or progression to myelofibrosis. In October 2011, at age 67, she presented with progressive cytopenia and an abrupt decline in platelets to 336 × 10⁹/L, accompanied by 14% blasts in peripheral blood. Bone marrow examination revealed hypercellularity with 76% leukemic blasts and increased megakaryocytes. Immunophenotyping confirmed a B-cell lineage phenotype (CD34+ CD19+ CD10+ HLA-DR+), and molecular analysis demonstrated monoclonal immunoglobulin heavy chain rearrangement. Cytogenetic and FISH studies identified the Philadelphia chromosome translocation t(9;22)(q34;q11.2) and monosomy 7. RT-PCR detected the minor BCR-ABL1 fusion transcript, confirming the diagnosis of Ph+ALL.
To determine clonal origins, mutational analysis was performed on granulocytes, lineage-negative CD34+ hematopoietic stem and progenitor cells (HSPCs), and CD34+CD19+ B-ALL cells.6-(4-Hydroxyphenoxy)hexyl custom synthesis JAK2-V617F mutation was present in granulocytes and HSPCs but absent in the B-ALL population, indicating that the Ph+ALL clone did not originate from the JAK2-mutated ET clone.Arterolane Activator Further investigation into the timing of BCR-ABL1 acquisition revealed that the minor transcript was detectable not only in committed B-cell precursors (CD34+CD19+CD10+) but also in the CD34+CD19−CD10− HSPC-enriched population, suggesting early acquisition prior to B-cell commitment.PMID:35228900 FISH confirmed the presence of the Philadelphia chromosome in 54% of CD34+CD19−CD10− cells and 10% of granulocytes.
The patient was treated with dasatinib and prednisolone. Four weeks later, blast counts declined significantly. However, RT-PCR analysis of sorted bone marrow subpopulations showed rapid disappearance of the minor BCR-ABL1 transcript in CD34+CD19− cells—likely representing primitive HSPCs—but persistence in CD34+CD19+ cells. Despite this, the transcript remained detectable at low levels in bulk bone marrow after ten weeks. Nine months post-treatment initiation, relapse occurred with the emergence of the T315I mutation, indicating selection of a resistant clone within the committed B-cell compartment rather than from the most primitive stem cells.
This case highlights the complexity of clonal evolution in MPN-associated leukemias. The absence of JAK2-V617F in Ph+ALL cells demonstrates that transformation to lymphoid leukemia can occur independently of the MPN clone. Moreover, the persistence of BCR-ABL1 in committed B-cells despite clearance in HSPCs challenges the assumption that resistance arises solely from quiescent stem cells. These findings suggest that the resistant clone may reside in differentiated populations, possibly due to microenvironmental protection or intrinsic resistance mechanisms. This observation bridges gaps between murine models and human disease, underscoring the need for deeper investigation into the biology of resistant clones in Ph+ALL patients undergoing TKI therapy.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com