Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical behavior are not fully understood. Here we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA sequencing data from 48 samples. We classified MCL into four robust clusters (C). C1 featured mutated IGHV, CCND1 mutation, amp(11q13) and active BCR signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-B and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1 and NSD2 with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q) and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these four clusters had distinct outcomes (5-year OS rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively, p<0.001). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

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