Page 103 - 2019_06-Haematologica-web

Cellular origin and clinical prognostic markers of infant MLLr B-ALL
of transgenic mice expressing human MLL-AF4 could be significantly accelerated by KRAS mutations. However, although activated KRAS did cooperate with MLL-AF4 in human cord blood-derived CD34+ HSPC to promote extramedullary infiltration and central nervous system infiltration it failed to initiate leukemia in engrafted mice.27 Importantly, we report a lack of correlation between RAS
A
B
status and parameters associated with diagnosis or disease outcome such as overall survival, event-free survival, cen- tral nervous system infiltration, gender, percentage of blasts and white blood cells and age, further supporting the concept that RAS mutations are not leukemia-initiat- ing/propagating lesions.
Clearly, this brings us back to the central question of
C
Figure 7. Comparison of the transcriptome of human fetal CD34+ hematopoietic stem and progenitor cell populations to infant B-cell precursor acute lymphoblastic leukemia. (A) Schematic representation of B-cell development in human fetal liver (FL) showing immunophenotypic definitions for hematopoi- etic stem cells (HSC), multipotent progenitors (MPP), lymphoid- primed multipotent progenitors (LMPP), committed B progeni- tors (CBP) and B cells. The onset and expected patterns of IgH rearrangements59,60 are depicted as red arrows. (B) Sorting strat- egy for FL hematopoietic stem and progenitor (HSPC) popula- tions by fluorescence-activated cell sorting. The sorting gates for each population are shown in representative flow plots on the left. The purity of the sorted populations is depicted on the right demonstrating >95% purity. (Lin, Lineage cocktail). (C) Principal component analysis of gene expression of infant B-cell precursor acute lymphoblastic leukemia (iBCP-ALL) samples (n=42) and FL HSPC populations (n=3-7) using the top 1,000 variably expressed genes, as determined by RNA-sequencing. FL HSPC as in (A); MAF4, MLL-AF4+ iBCP-ALL; MA9, MLL-AF9+ iBCP-ALL; MLLwt, MLL wildtype iBCP-ALL.
haematologica | 2019; 104(6)
1185