Stem and progenitor cell involvement in acute lymphoblastic leukemia
Abstract: Leukemic stem cells (LSCs) share the capacity of self renewal and extensive proliferation with normal hematopoietic stem cells (HSCs), and are therefore obvious targets for therapy. As such, they need to be identified and characterized in order to elucidate what drives them, and what separates them from their normal counterparts. The focus of this thesis is on pre B cell Acute Lymphoblastic Leukemia (ALL), the most common form of cancer in children. We have investigated 2 distinct subtypes of ALL, characterized by the gene fusions ETV6-RUNX1 (found mainly in pediatric ALL, conferring a favorable prognosis) and BCR-ABL1 (producing two different onco-proteins, designated P190 and P210, both of which are associated with a poor prognosis in both children and adults). We show that ETV6-RUNX1 ALL are propagated by B-cell committed LSCs expressing the lymphoid marker CD19, leaving the normal HSC compartment intact. In BCR-ABL1-positive ALL we show an unexpected difference between the two forms of the fusion protein, such that the LSC in P190 BCR-ABL1 ALL, similar to ETV6-RUNX1 ALL, are B-cell committed progenitors, whereas P210 BCR-ABL1 ALL originates in a multipotent HSC, expressing the same phenotypical markers as the normal HSC, and with a retained, albeit severely reduced, capacity to produce a clonal myeloid progeny. Interestingly, the LSC still displays the B cell commitment marker CD19, as only CD19+ cells propagates the disease in immunocompromised mice. We cannot, however, exclude very rare, and/or very quiscent CD19-ve P210 LSCs. This represents a hitherto unanticipated distinct biological difference between P190 and P210 ALLs, possibly indicating different requirements for eradication. In the second paper we describe a method to prospectively purify a large part of the leukemic cells from bone marrow or peripheral blood from patients with ALL, for relevant comparisons across samples. We compared ALL cells harvested from bone marrow and peripheral blood from the same patient by gene expression profiling, and found a striking similarity between cells from the two locations, indicating that bone marrow derived biological cues necessary for normal pre B cells not seem to segregate ALL cells in a blood and a bone marrow compartment, and that cells thus can be harvested from either compartment for further gene expression analyses. Finally, in the discussion part of the two papers, are preliminary data from follow up studies discussed, where we find indications for the existence of distinct sets of LSCs within the same patient with ALL or chronic myeloid leukemia in lymphoid blast crisis, contrary to the generally held view of a homogeneous LSC population.
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